Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Epigenetic regulation of pediatric and neonatal immune responses

Abstract

Epigenetic regulation of transcription is a collective term that refers to mechanisms known to regulate gene transcription without changing the underlying DNA sequence. These mechanisms include DNA methylation and histone tail modifications which influence chromatin accessibility, and microRNAs that act through post-transcriptional gene silencing. Epigenetics is known to regulate a variety of biological processes, and the role of epigtenetics in immunity and immune-mediated diseases is becoming increasingly recognized. While DNA methylation is the most widely studied, each of these systems play an important role in the development and maintenance of appropriate immune responses. There is clear evidence that epigenetic mechanisms contribute to developmental stage-specific immune responses in a cell-specific manner. There is also mounting evidence that prenatal exposures alter epigenetic profiles and subsequent immune function in exposed offspring. Early life exposures that are associated with poor long-term health outcomes also appear to impact immune specific epigenetic patterning. Finally, each of these epigenetic mechanisms contribute to the pathogenesis of a wide variety of diseases that manifest during childhood. This review will discuss each of these areas in detail.

Impact

  • Epigenetics, including DNA methylation, histone tail modifications, and microRNA expression, dictate immune cell phenotypes.

  • Epigenetics influence immune development and subsequent immune health.

  • Prenatal, perinatal, and postnatal exposures alter immune cell epigenetic profiles and subsequent immune function.

  • Numerous pediatric-onset diseases have an epigenetic component.

  • Several successful strategies for childhood diseases target epigenetic mechanisms.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Epigenetic regulation of gene expression.
Fig. 2: Article table of contents by section.
Fig. 3: Summary of global DNA methylation and histone tail modification changes in immune cells over the course of development from preterm neonate to adult.
Fig. 4: Schematic representation of offspring DNA methylation and histone tail modification changes following prenatal exposures.
Fig. 5: Summary of the impact of early life exposures on DNA methylation and histone tail modifications throughout childhood.
Fig. 6: Schematic representation of DNA methylation and histone tail modification changes in childhood onset diseases at key pro-inflammatory (Th1), atopic (Th2), and regulatory (Treg) immune genes.

References

  1. Zemach, A., McDaniel, I. E., Silva, P. & Zilberman, D. Genome-wide evolutionary analysis of eukaryotic DNA methylation. Science 328, 916–919 (2010).

    CAS  PubMed  Google Scholar 

  2. Greenberg, M. V. C. & Bourc’his, D. The diverse roles of DNA methylation in mammalian development and disease. Nat. Rev. Mol. Cell Biol. 20, 590–607 (2019).

    CAS  PubMed  Google Scholar 

  3. Sawan, C. & Herceg, Z. Histone modifications and cancer. Adv. Genet. 70, 57–85 (2010).

    CAS  PubMed  Google Scholar 

  4. Ramazi, S., Allahverdi, A. & Zahiri, J. Evaluation of post-translational modifications in histone proteins: a review on histone modification defects in developmental and neurological disorders. J. Biosci. 45, 135 (2020).

  5. Anglicheau, D., Muthukumar, T. & Suthanthiran, M. MicroRNAs: small RNAs with big effects. Transplantation 90, 105–112 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Ha, M. & Kim, V. N. Regulation of microRNA biogenesis. Nat. Rev. Mol. Cell Biol. 15, 509–524 (2014).

    CAS  PubMed  Google Scholar 

  7. Vasudevan, S. Posttranscriptional upregulation by microRNAs. Wiley Interdiscip. Rev. RNA 3, 311–330 (2012).

    CAS  PubMed  Google Scholar 

  8. Paul, P. et al. Interplay between miRNAs and human diseases. J. Cell. Physiol. 233, 2007–2018 (2018).

    CAS  PubMed  Google Scholar 

  9. Condrat, C. E. et al. miRNAs as biomarkers in disease: latest findings regarding their role in diagnosis and prognosis. Cells 9, 276 (2020).

  10. Tzika, E., Dreker, T. & Imhof, A. Epigenetics and metabolism in health and disease. Front. Genet. 9, 361 (2018).

    PubMed  PubMed Central  Google Scholar 

  11. Sharma, S., Kelly, T. K. & Jones, P. A. Epigenetics in cancer. Carcinogenesis 31, 27–36 (2010).

    CAS  PubMed  Google Scholar 

  12. Busslinger, M. & Tarakhovsky, A. Epigenetic control of immunity. Cold Spring Harb. Perspect. Biol. 6, a019307 (2014).

  13. Simonsen, K. A., Anderson-Berry, A. L., Delair, S. F. & Davies, H. D. Early-onset neonatal sepsis. Clin. Microbiol. Rev. 27, 21–47 (2014).

    PubMed  PubMed Central  Google Scholar 

  14. Tatad, A. M. et al. Cytokine expression in response to bacterial antigens in preterm and term infant cord blood monocytes. Neonatology 94, 8–15 (2008).

    CAS  PubMed  Google Scholar 

  15. Michels, K. B., Harris, H. R. & Barault, L. Birthweight, maternal weight trajectories and global DNA methylation of LINE-1 repetitive elements. PLoS ONE 6, e25254 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Cruickshank, M. N. et al. Analysis of epigenetic changes in survivors of preterm birth reveals the effect of gestational age and evidence for a long term legacy. Genome Med. 5, 96 (2013).

    PubMed  PubMed Central  Google Scholar 

  17. Wu, Y. et al. Analysis of two birth tissues provides new insights into the epigenetic landscape of neonates born preterm. Clin. Epigenetics 11, 26 (2019).

    PubMed  PubMed Central  Google Scholar 

  18. de Goede, O. M., Lavoie, P. M. & Robinson, W. P. Cord blood hematopoietic cells from preterm infants display altered DNA methylation patterns. Clin. Epigenetics 9, 39 (2017).

    PubMed  PubMed Central  Google Scholar 

  19. Merid, S. K. et al. Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age. Genome Med. 12, 25 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Simpkin, A. J. et al. Longitudinal analysis of DNA methylation associated with birth weight and gestational age. Hum. Mol. Genet. 24, 3752–3763 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Spada, E. et al. Epigenome wide association and stochastic epigenetic mutation analysis on cord blood of preterm birth. Int. J. Mol. Sci. 21, 5044 (2020).

  22. Hannon, E. et al. Variable DNA methylation in neonates mediates the association between prenatal smoking and birth weight. Philos. Trans. R. Soc. Lond. B Biol. Sci. 374, 20180120 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Bohlin, J. et al. Prediction of gestational age based on genome-wide differentially methylated regions. Genome Biol. 17, 207 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. McCarthy, J. M. et al. Umbilical cord nucleated red blood cell counts: normal values and the effect of labor. J. Perinatol. 26, 89–92 (2006).

    CAS  PubMed  Google Scholar 

  25. Ji, H. et al. Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature 467, 338–342 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Álvarez-Errico, D., Vento-Tormo, R., Sieweke, M. & Ballestar, E. Epigenetic control of myeloid cell differentiation, identity and function. Nat. Rev. Immunol. 15, 7–17 (2015).

    PubMed  Google Scholar 

  27. Yu, Y. et al. High resolution methylome analysis reveals widespread functional hypomethylation during adult human erythropoiesis. J. Biol. Chem. 288, 8805–8814 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Bermick, J. R. et al. Neonatal monocytes exhibit a unique histone modification landscape. Clin. Epigenetics 8, 99 (2016).

    PubMed  PubMed Central  Google Scholar 

  29. Zea-Vera, A. & Ochoa, T. J. Challenges in the diagnosis and management of neonatal sepsis. J. Trop. Pediatr. 61, 1–13 (2015).

    PubMed  PubMed Central  Google Scholar 

  30. Alisch, R. S. et al. Age-associated DNA methylation in pediatric populations. Genome Res. 22, 623–632 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Urdinguio, R. G. et al. Longitudinal study of DNA methylation during the first 5 years of life. J. Transl. Med. 14, 160 (2016).

    PubMed  PubMed Central  Google Scholar 

  32. Pischedda, S. et al. Changes in epigenetic profiles throughout early childhood and their relationship to the response to pneumococcal vaccination. Clin. Epigenetics 13, 29 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Mulder, R. H. et al. Epigenome-wide change and variation in DNA methylation in childhood: trajectories from birth to late adolescence. Hum. Mol. Genet. 30, 119–134 (2021).

  34. Hayashi, I. et al. Full-term low birth weight infants have differentially hypermethylated DNA related to immune system and organ growth: a comparison with full-term normal birth weight infants. BMC Res. Notes 13, 199 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Li, J. et al. Impaired NK cell antiviral cytokine response against influenza virus in small-for-gestational-age neonates. Cell. Mol. Immunol. 10, 437–443 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Acevedo, N. et al. Age-associated DNA methylation changes in immune genes, histone modifiers and chromatin remodeling factors within 5 years after birth in human blood leukocytes. Clin. Epigenetics 7, 34 (2015).

    PubMed  PubMed Central  Google Scholar 

  37. Gutierrez, M. J., Nino, G., Hong, X. & Wang, X. Epigenetic dynamics of the infant immune system reveals a tumor necrosis factor superfamily signature in early human life. Epigenomes 4, 12 (2020).

  38. Jacoby, M. et al. Interindividual variability and co-regulation of DNA methylation differ among blood cell populations. Epigenetics 7, 1421–1434 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Martino, D. J. et al. Evidence for age-related and individual-specific changes in DNA methylation profile of mononuclear cells during early immune development in humans. Epigenetics 6, 1085–1094 (2011).

    CAS  PubMed  Google Scholar 

  40. Herbstman, J. B. et al. Predictors and consequences of global DNA methylation in cord blood and at three years. PLoS ONE 8, e72824 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Thompson, E. E. et al. Global DNA methylation changes spanning puberty are near predicted estrogen-responsive genes and enriched for genes involved in endocrine and immune processes. Clin. Epigenetics 10, 62 (2018).

    PubMed  PubMed Central  Google Scholar 

  42. Huen, K. et al. Age-related differences in miRNA expression in Mexican-American newborns and children. Int. J. Environ. Res. Public Health. 16, 524 (2019).

  43. Prentice, S. et al. BCG-induced non-specific effects on heterologous infectious disease in Ugandan neonates: an investigator-blind randomised controlled trial. Lancet Infect. Dis. 21, 993–1003 (2021).

  44. Zhao, M. et al. Distinct epigenomes in CD4(+) T cells of newborns, middle-ages and centenarians. Sci. Rep. 6, 38411 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Dobbs, K. R. et al. Age-related differences in monocyte DNA methylation and immune function in healthy Kenyan adults and children. Immun. Ageing 18, 11 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Cheung, P. et al. Single-cell chromatin modification profiling reveals increased epigenetic variations with aging. Cell 173, 1385–1397. e1314 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Merkerova, M., Vasikova, A., Belickova, M. & Bruchova, H. MicroRNA expression profiles in umbilical cord blood cell lineages. Stem Cells Dev. 19, 17–26 (2010).

    CAS  PubMed  Google Scholar 

  48. Yu, H. R. et al. Comparison of the functional microRNA expression in immune cell subsets of neonates and adults. Front. Immunol. 7, 615 (2016).

    PubMed  PubMed Central  Google Scholar 

  49. Takahashi, N., Nakaoka, T. & Yamashita, N. Profiling of immune-related microRNA expression in human cord blood and adult peripheral blood cells upon proinflammatory stimulation. Eur. J. Haematol. 88, 31–38 (2012).

    CAS  PubMed  Google Scholar 

  50. Kim, S. Y. et al. Methylome of fetal and maternal monocytes and macrophages at the feto-maternal interface. Am. J. Reprod. Immunol. 68, 8–27 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Lederhuber, H. et al. MicroRNA-146: tiny player in neonatal innate immunity? Neonatology 99, 51–56 (2011).

    CAS  PubMed  Google Scholar 

  52. Huang, H. C. et al. miRNA-125b regulates TNF-α production in CD14+ neonatal monocytes via post-transcriptional regulation. J. Leukoc. Biol. 92, 171–182 (2012).

    CAS  PubMed  Google Scholar 

  53. Huang, H. C. et al. MicroRNA-142-3p and let-7g negatively regulates augmented IL-6 production in neonatal polymorphonuclear leukocytes. Int. J. Biol. Sci. 13, 690–700 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Jacometo, C. B. et al. Maternal supply of methionine during late pregnancy is associated with changes in immune function and abundance of microRNA and mRNA in Holstein calf polymorphonuclear leukocytes. J. Dairy Sci. 101, 8146–8158 (2018).

    CAS  PubMed  Google Scholar 

  55. Dindot, S. V. et al. Postnatal changes in epigenetic modifications of neutrophils of foals are associated with increased ROS function and regulation of neutrophil function. Dev. Comp. Immunol. 87, 182–187 (2018).

    CAS  PubMed  Google Scholar 

  56. Charrier, E. et al. Post-transcriptional down-regulation of Toll-like receptor signaling pathway in umbilical cord blood plasmacytoid dendritic cells. Cell. Immunol. 276, 114–121 (2012).

    CAS  PubMed  Google Scholar 

  57. Yoshimoto, M., Yoder, M. C., Guevara, P. & Adkins, B. The murine Th2 locus undergoes epigenetic modification in the thymus during fetal and postnatal ontogeny. PLoS ONE 8, e51587 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Rose, S., Lichtenheld, M., Foote, M. R. & Adkins, B. Murine neonatal CD4 + cells are poised for rapid Th2 effector-like function. J. Immunol. 178, 2667–2678 (2007).

    CAS  PubMed  Google Scholar 

  59. Martino, D. et al. Genome-scale profiling reveals a subset of genes regulated by DNA methylation that program somatic T-cell phenotypes in humans. Genes Immun. 13, 388–398 (2012).

    CAS  PubMed  Google Scholar 

  60. Forsberg, A. et al. Pre- and postnatal Lactobacillus reuteri treatment alters DNA methylation of infant T helper cells. Pediatr. Allergy Immunol. 31, 544–553 (2020).

    CAS  PubMed  Google Scholar 

  61. White, G. P., Watt, P. M., Holt, B. J. & Holt, P. G. Differential patterns of methylation of the IFN-gamma promoter at CpG and non-CpG sites underlie differences in IFN-gamma gene expression between human neonatal and adult CD45RO- T cells. J. Immunol. 168, 2820–2827 (2002).

    CAS  PubMed  Google Scholar 

  62. Weitzel, R. P. et al. microRNA 184 regulates expression of NFAT1 in umbilical cord blood CD4+ T cells. Blood 113, 6648–6657 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Palin, A. C., Ramachandran, V., Acharya, S. & Lewis, D. B. Human neonatal naive CD4+ T cells have enhanced activation-dependent signaling regulated by the microRNA miR-181a. J. Immunol. 190, 2682–2691 (2013).

    CAS  PubMed  Google Scholar 

  64. Ramming, A. et al. Maturation-related histone modifications in the PU.1 promoter regulate Th9-cell development. Blood 119, 4665–4674 (2012).

    CAS  PubMed  Google Scholar 

  65. Smith, N. L. et al. Developmental origin governs CD8(+) T cell fate decisions during infection. Cell 174, 117–130.e114 (2018).

    CAS  PubMed  Google Scholar 

  66. Wells, A. C. et al. Modulation of let-7 miRNAs controls the differentiation of effector CD8 T cells. Elife. 6, 326398 (2017).

  67. Wissink, E. M. et al. MicroRNAs and their targets are differentially regulated in adult and neonatal mouse CD8+ T cells. Genetics 201, 1017–1030 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Galindo-Albarrán, A. O. et al. CD8(+) T cells from human neonates are biased toward an innate immune response. Cell Rep. 17, 2151–2160 (2016).

    PubMed  Google Scholar 

  69. D’Addio, F. et al. The link between the PDL1 costimulatory pathway and Th17 in fetomaternal tolerance. J. Immunol. 187, 4530–4541 (2011).

    PubMed  Google Scholar 

  70. Guleria, I. et al. A critical role for the programmed death ligand 1 in fetomaternal tolerance. J. Exp. Med. 202, 231–237 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Habicht, A. et al. A link between PDL1 and T regulatory cells in fetomaternal tolerance. J. Immunol. 179, 5211–5219 (2007).

    CAS  PubMed  Google Scholar 

  72. Hsu, H. et al. Prolonged PD1 expression on neonatal Vδ2 lymphocytes dampens proinflammatory responses: role of epigenetic regulation. J. Immunol. 197, 1884–1892 (2016).

    CAS  PubMed  Google Scholar 

  73. Glaesener, S. et al. Decreased production of class-switched antibodies in neonatal B cells is associated with increased expression of miR-181b. PLoS ONE 13, e0192230 (2018).

    PubMed  PubMed Central  Google Scholar 

  74. Heijmans, B. T. et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc. Natl Acad. Sci. USA 105, 17046–17049 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. He, Y. et al. DNA methylation changes related to nutritional deprivation: a genome-wide analysis of population and in vitro data. Clin. Epigenetics 11, 80 (2019).

    PubMed  PubMed Central  Google Scholar 

  76. Robinson, S. M. et al. Modifiable early-life risk factors for childhood adiposity and overweight: an analysis of their combined impact and potential for prevention. Am. J. Clin. Nutr. 101, 368–375 (2015).

    CAS  PubMed  Google Scholar 

  77. McEvoy, C. T. & Spindel, E. R. Pulmonary effects of maternal smoking on the fetus and child: effects on lung development, respiratory morbidities, and life long lung health. Paediatr. Respir. Rev. 21, 27–33 (2017).

    PubMed  Google Scholar 

  78. Huang, L. et al. Maternal smoking and attention-deficit/hyperactivity disorder in offspring: a meta-analysis. Pediatrics 141, e20172465 (2018).

  79. Joubert, B. R. et al. DNA methylation in newborns and maternal smoking in pregnancy: genome-wide consortium meta-analysis. Am. J. Hum. Genet. 98, 680–696 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Küpers, L. K. et al. DNA methylation mediates the effect of maternal smoking during pregnancy on birthweight of the offspring. Int. J. Epidemiol. 44, 1224–1237 (2015).

    PubMed  PubMed Central  Google Scholar 

  81. Richmond, R. C. et al. Prenatal exposure to maternal smoking and offspring DNA methylation across the lifecourse: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC). Hum. Mol. Genet. 24, 2201–2217 (2015).

    CAS  PubMed  Google Scholar 

  82. Ladd-Acosta, C. et al. Presence of an epigenetic signature of prenatal cigarette smoke exposure in childhood. Environ. Res. 144, 139–148 (2016).

    CAS  PubMed  Google Scholar 

  83. Wang, I. J. et al. Prenatal smoke exposure, DNA methylation, and childhood atopic dermatitis. Clin. Exp. Allergy 43, 535–543 (2013).

    CAS  PubMed  Google Scholar 

  84. Venkatakrishnan, K., Von Moltke, L. L. & Greenblatt, D. J. Human drug metabolism and the cytochromes P450: application and relevance of in vitro models. J. Clin. Pharmacol. 41, 1149–1179 (2001).

    CAS  PubMed  Google Scholar 

  85. Olety, B. et al. Myosin 1G (Myo1G) is a haematopoietic specific myosin that localises to the plasma membrane and regulates cell elasticity. FEBS Lett. 584, 493–499 (2010).

    CAS  PubMed  Google Scholar 

  86. Phelan, J. D. et al. Gfi1-cells and circuits: unraveling transcriptional networks of development and disease. Curr. Opin. Hematol. 17, 300–307 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Shimoda, Y. & Watanabe, K. Contactins: emerging key roles in the development and function of the nervous system. Cell Adh. Migr. 3, 64–70 (2009).

    PubMed  PubMed Central  Google Scholar 

  88. Wu, C. C. et al. Paternal tobacco smoke correlated to offspring asthma and prenatal epigenetic programming. Front. Genet. 10, 471 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Herberth, G. et al. Maternal and cord blood miR-223 expression associates with prenatal tobacco smoke exposure and low regulatory T-cell numbers. J. Allergy Clin. Immunol. 133, 543–550 (2014).

    CAS  PubMed  Google Scholar 

  90. Grandjean, P. et al. Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol. Teratol. 19, 417–428 (1997).

    CAS  PubMed  Google Scholar 

  91. Sagiv, S. K. et al. Prenatal exposure to mercury and fish consumption during pregnancy and attention-deficit/hyperactivity disorder-related behavior in children. Arch. Pediatr. Adolesc. Med. 166, 1123–1131 (2012).

    PubMed  PubMed Central  Google Scholar 

  92. Tolins, M., Ruchirawat, M. & Landrigan, P. The developmental neurotoxicity of arsenic: cognitive and behavioral consequences of early life exposure. Ann. Glob. Health 80, 303–314 (2014).

    PubMed  Google Scholar 

  93. Cardenas, A. et al. Differential DNA methylation in umbilical cord blood of infants exposed to mercury and arsenic in utero. Epigenetics 10, 508–515 (2015).

    PubMed  PubMed Central  Google Scholar 

  94. Kile, M. L. et al. Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood. Epigenetics 9, 774–782 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Rager, J. E. et al. Prenatal arsenic exposure and the epigenome: altered microRNAs associated with innate and adaptive immune signaling in newborn cord blood. Environ. Mol. Mutagen. 55, 196–208 (2014).

    CAS  PubMed  Google Scholar 

  96. Starling, A. P. et al. Prenatal exposure to per- and polyfluoroalkyl substances and infant growth and adiposity: the Healthy Start Study. Environ. Int. 131, 104983 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Ait Bamai, Y. et al. Effect of prenatal exposure to per- and polyfluoroalkyl substances on childhood allergies and common infectious diseases in children up to age 7 years: The Hokkaido study on environment and children’s health. Environ. Int. 143, 105979 (2020).

    CAS  PubMed  Google Scholar 

  98. Starling, A. P. et al. Prenatal exposure to per- and polyfluoroalkyl substances, umbilical cord blood DNA methylation, and cardio-metabolic indicators in newborns: The Healthy Start Study. Environ. Health Perspect. 128, 127014 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Woods, R. et al. Long-lived epigenetic interactions between perinatal PBDE exposure and Mecp2308 mutation. Hum. Mol. Genet. 21, 2399–2411 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Ta, T. A. et al. Bioaccumulation and behavioral effects of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) in perinatally exposed mice. Neurotoxicol. Teratol. 33, 393–404 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Dao, T., Hong, X., Wang, X. & Tang, W. Y. Aberrant 5’-CpG methylation of cord blood TNFα associated with maternal exposure to polybrominated diphenyl ethers. PLoS ONE 10, e0138815 (2015).

    PubMed  PubMed Central  Google Scholar 

  102. Guarnieri, M. & Balmes, J. R. Outdoor air pollution and asthma. Lancet 383, 1581–1592 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Gruzieva, O. et al. Epigenome-wide meta-analysis of methylation in children related to prenatal NO2 air pollution exposure. Environ. Health Perspect. 125, 104–110 (2017).

    CAS  PubMed  Google Scholar 

  104. Tang, W. Y. et al. Maternal exposure to polycyclic aromatic hydrocarbons and 5’-CpG methylation of interferon-γ in cord white blood cells. Environ. Health Perspect. 120, 1195–1200 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Perera, F. et al. Relation of DNA methylation of 5’-CpG island of ACSL3 to transplacental exposure to airborne polycyclic aromatic hydrocarbons and childhood asthma. PLoS ONE 4, e4488 (2009).

    PubMed  PubMed Central  Google Scholar 

  106. Fetahu, I. S., Höbaus, J. & Kállay, E. Vitamin D and the epigenome. Front. Physiol. 5, 164 (2014).

    PubMed  PubMed Central  Google Scholar 

  107. Jiao, X. et al. Vitamin D deficiency during pregnancy affects the function of Th1/Th2 cells and methylation of IFN-γ gene in offspring rats. Immunol. Lett. 212, 98–105 (2019).

    CAS  PubMed  Google Scholar 

  108. Anderson, C. M. et al. Effects of maternal vitamin D supplementation on the maternal and infant epigenome. Breastfeed. Med. 13, 371–380 (2018).

    PubMed  PubMed Central  Google Scholar 

  109. Irwin, R. E. et al. The interplay between DNA methylation, folate and neurocognitive development. Epigenomics 8, 863–879 (2016).

    CAS  PubMed  Google Scholar 

  110. Schaible, T. D. et al. Maternal methyl-donor supplementation induces prolonged murine offspring colitis susceptibility in association with mucosal epigenetic and microbiomic changes. Hum. Mol. Genet. 20, 1687–1696 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Amarasekera, M. et al. Genome-wide DNA methylation profiling identifies a folate-sensitive region of differential methylation upstream of ZFP57-imprinting regulator in humans. FASEB J. 28, 4068–4076 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Harb, H. et al. Epigenetic regulation in early childhood: a miniaturized and validated method to assess histone acetylation. Int. Arch. Allergy Immunol. 168, 173–181 (2015).

    CAS  PubMed  Google Scholar 

  113. D’Vaz, N. et al. Fish oil supplementation in early infancy modulates developing infant immune responses. Clin. Exp. Allergy 42, 1206–1216 (2012).

    PubMed  Google Scholar 

  114. Dunstan, J. A. et al. Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at high risk of atopy: a randomized, controlled trial. J. Allergy Clin. Immunol. 112, 1178–1184 (2003).

    CAS  PubMed  Google Scholar 

  115. Tremblay, B. L. et al. Epigenetic changes in blood leukocytes following an omega-3 fatty acid supplementation. Clin. Epigenetics 9, 43 (2017).

    PubMed  PubMed Central  Google Scholar 

  116. Losol, P. et al. Effect of gestational oily fish intake on the risk of allergy in children may be influenced by FADS1/2, ELOVL5 expression and DNA methylation. Genes Nutr. 14, 20 (2019).

    PubMed  PubMed Central  Google Scholar 

  117. Bianchi, M. et al. Maternal intake of n-3 polyunsaturated fatty acids during pregnancy is associated with differential methylation profiles in cord blood white cells. Front. Genet. 10, 1050 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. van Dijk, S. J. et al. Effect of prenatal DHA supplementation on the infant epigenome: results from a randomized controlled trial. Clin. Epigenetics 8, 114 (2016).

    PubMed  PubMed Central  Google Scholar 

  119. Amarasekera, M. et al. Epigenome-wide analysis of neonatal CD4(+) T-cell DNA methylation sites potentially affected by maternal fish oil supplementation. Epigenetics 9, 1570–1576 (2014).

    PubMed  PubMed Central  Google Scholar 

  120. Harb, H. et al. The role of PKCζ in cord blood T-cell maturation towards Th1 cytokine profile and its epigenetic regulation by fish oil. Biosci. Rep. 37, BSR20160485 (2017).

  121. Godfrey, K. M. et al. Influence of maternal obesity on the long-term health of offspring. Lancet Diabetes Endocrinol. 5, 53–64 (2017).

    PubMed  Google Scholar 

  122. Sharp, G. C. et al. Maternal pre-pregnancy BMI and gestational weight gain, offspring DNA methylation and later offspring adiposity: findings from the Avon Longitudinal Study of Parents and Children. Int. J. Epidemiol. 44, 1288–1304 (2015).

    PubMed  PubMed Central  Google Scholar 

  123. Liu, X. et al. Maternal preconception body mass index and offspring cord blood DNA methylation: exploration of early life origins of disease. Environ. Mol. Mutagen. 55, 223–230 (2014).

    CAS  PubMed  Google Scholar 

  124. Burris, H. H. et al. Offspring DNA methylation of the aryl-hydrocarbon receptor repressor gene is associated with maternal BMI, gestational age, and birth weight. Epigenetics 10, 913–921 (2015).

    PubMed  PubMed Central  Google Scholar 

  125. Morales, E., Groom, A., Lawlor, D. A. & Relton, C. L. DNA methylation signatures in cord blood associated with maternal gestational weight gain: results from the ALSPAC cohort. BMC Res. Notes 7, 278 (2014).

    PubMed  PubMed Central  Google Scholar 

  126. Lawlor, D. A., Relton, C., Sattar, N. & Nelson, S. M. Maternal adiposity—a determinant of perinatal and offspring outcomes? Nat. Rev. Endocrinol. 8, 679–688 (2012).

    PubMed  Google Scholar 

  127. Sureshchandra, S. et al. Maternal pregravid obesity remodels the DNA methylation landscape of cord blood monocytes disrupting their inflammatory program. J. Immunol. 199, 2729–2744 (2017).

    CAS  PubMed  Google Scholar 

  128. Cifuentes-Zúñiga, F. et al. IL-10 expression in macrophages from neonates born from obese mothers is suppressed by IL-4 and LPS/INFγ. J. Cell. Physiol. 232, 3693–3701 (2017).

    PubMed  Google Scholar 

  129. Vega-Tapia, F. et al. Maternal obesity is associated with a sex-specific epigenetic programming in human neonatal monocytes. Epigenomics 12, 1999–2018 (2020).

    CAS  PubMed  Google Scholar 

  130. Weng, X. et al. Genome-wide DNA methylation profiling in infants born to gestational diabetes mellitus. Diabetes Res. Clin. Pract. 142, 10–18 (2018).

    CAS  PubMed  Google Scholar 

  131. Méndez-Mancilla, A. et al. Differential expression profiles of circulating microRNAs in newborns associated to maternal pregestational overweight and obesity. Pediatr. Obes. 13, 168–174 (2018).

    PubMed  Google Scholar 

  132. Ghaffari, N., Parry, S., Elovitz, M. A. & Durnwald, C. P. The Effect of an obesogenic maternal environment on expression of fetal umbilical cord blood miRNA. Reprod. Sci. 22, 860–864 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Geraghty, A. A. et al. A low glycaemic index diet in pregnancy induces dna methylation variation in blood of newborns: results from the ROLO Randomised Controlled Trial. Nutrients 10, 455 (2018).

  134. Guénard, F. et al. Methylation and expression of immune and inflammatory genes in the offspring of bariatric bypass surgery patients. J. Obes. 2013, 492170 (2013).

    PubMed  PubMed Central  Google Scholar 

  135. Knoop, J. et al. Maternal Type 1 diabetes reduces autoantigen-responsive CD4(+) T cells in offspring. Diabetes 69, 661–669 (2020).

    CAS  PubMed  Google Scholar 

  136. Lazdam, M. et al. Elevated blood pressure in offspring born premature to hypertensive pregnancy: is endothelial dysfunction the underlying vascular mechanism? Hypertension 56, 159–165 (2010).

    CAS  PubMed  Google Scholar 

  137. Davis, E. F. et al. Clinical cardiovascular risk during young adulthood in offspring of hypertensive pregnancies: insights from a 20-year prospective follow-up birth cohort. BMJ Open 5, e008136 (2015).

    PubMed  PubMed Central  Google Scholar 

  138. Yu, G. Z. et al. Neonatal micro-RNA profile determines endothelial function in offspring of hypertensive pregnancies. Hypertension 72, 937–945 (2018).

    CAS  PubMed  Google Scholar 

  139. Nemoda, Z. et al. Maternal depression is associated with DNA methylation changes in cord blood T lymphocytes and adult hippocampi. Transl. Psychiatry 5, e545 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Cao-Lei, L. et al. DNA methylation mediates the impact of exposure to prenatal maternal stress on BMI and central adiposity in children at age 13½ years: Project Ice Storm. Epigenetics 10, 749–761 (2015).

    PubMed  PubMed Central  Google Scholar 

  141. Dancause, K. N. et al. Prenatal stress due to a natural disaster predicts adiposity in childhood: the Iowa Flood Study. J. Obes. 2015, 570541 (2015).

    PubMed  PubMed Central  Google Scholar 

  142. Li, J. et al. Prenatal stress exposure related to maternal bereavement and risk of childhood overweight. PLoS ONE 5, e11896 (2010).

    PubMed  PubMed Central  Google Scholar 

  143. Wu, S. et al. Prenatal stress, methylation in inflammation-related genes, and adiposity measures in early childhood: the Programming Research in Obesity, Growth Environment and Social Stress Cohort Study. Psychosom. Med. 80, 34–41 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Ramo-Fernández, L. et al. The effects of childhood maltreatment on epigenetic regulation of stress-response associated genes: an intergenerational approach. Sci. Rep. 9, 983 (2019).

    PubMed  PubMed Central  Google Scholar 

  145. Ege, M. J. et al. Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children. J. Allergy Clin. Immunol. 117, 817–823 (2006).

    PubMed  Google Scholar 

  146. Braun-Fahrländer, C. et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N. Engl. J. Med. 347, 869–877 (2002).

    PubMed  Google Scholar 

  147. Schaub, B. et al. Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells. J. Allergy Clin. Immunol. 123, 774–782. e775 (2009).

    CAS  PubMed  Google Scholar 

  148. Bermick, J. et al. Chorioamnionitis exposure remodels the unique histone modification landscape of neonatal monocytes and alters the expression of immune pathway genes. FEBS J. 286, 82–109 (2019).

    CAS  PubMed  Google Scholar 

  149. Kumar, R. et al. Prematurity, chorioamnionitis, and the development of recurrent wheezing: a prospective birth cohort study. J. Allergy Clin. Immunol. 121, 878–884.e876 (2008) .

    PubMed  PubMed Central  Google Scholar 

  150. Garcia-Munoz Rodrigo, F., Galan Henriquez, G., Figueras Aloy, J. & Garcia-Alix Perez, A. Outcomes of very-low-birth-weight infants exposed to maternal clinical chorioamnionitis: a multicentre study. Neonatology 106, 229–234 (2014).

    PubMed  Google Scholar 

  151. McCullough, L. E. et al. Maternal inflammatory diet and adverse pregnancy outcomes: circulating cytokines and genomic imprinting as potential regulators? Epigenetics 12, 688–697 (2017).

    PubMed  PubMed Central  Google Scholar 

  152. Al-Rugeebah, A., Alanazi, M. & Parine, N. R. MEG3: an oncogenic long non-coding RNA in different cancers. Pathol. Oncol. Res. 25, 859–874 (2019).

    CAS  PubMed  Google Scholar 

  153. Fong, G. et al. DNA methylation profile in human cord blood mononuclear leukocytes from term neonates: effects of histological chorioamnionitis. Front. Pediatr. 8, 437 (2020).

    PubMed  PubMed Central  Google Scholar 

  154. Lee, J. et al. Increased miR-223 expression in foetal organs is a signature of acute chorioamnionitis with systemic consequences. J. Cell. Mol. Med. 22, 1179–1189 (2018).

    CAS  PubMed  Google Scholar 

  155. Tsitsiou, E. & Lindsay, M. A. microRNAs and the immune response. Curr. Opin. Pharmacol. 9, 514–520 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Phillips, N. et al. HIV-associated cognitive impairment in perinatally infected children: a meta-analysis. Pediatrics. 138, e20160893 (2016).

  157. Aldrovandi, G. M. et al. Morphologic and metabolic abnormalities in vertically HIV-infected children and youth. AIDS 23, 661–672 (2009).

    PubMed  Google Scholar 

  158. Unsal, A. B. et al. Effect of antiretroviral therapy on bone and renal health in young adults infected with HIV in early life. J. Clin. Endocrinol. Metab. 102, 2896–2904 (2017).

    PubMed  PubMed Central  Google Scholar 

  159. Shiau, S. et al. Distinct epigenetic profiles in children with perinatally-acquired HIV on antiretroviral therapy. Sci. Rep. 9, 10495 (2019).

    PubMed  PubMed Central  Google Scholar 

  160. Wheeler, A. C. Development of infants with congenital Zika syndrome: what do we know and what can we expect? Pediatrics 141, S154–S160 (2018).

    PubMed  PubMed Central  Google Scholar 

  161. Anderson, D. et al. Zika virus changes methylation of genes involved in immune response and neural development in Brazilian babies born with congenital microcephaly. J. Infect. Dis. 223, 435–440 (2021).

    CAS  PubMed  Google Scholar 

  162. Qu, F. et al. Ankyrin-B is a PI3P effector that promotes polarized α5β1-integrin recycling via recruiting RabGAP1L to early endosomes. Elife. 5, e20417 (2016).

  163. Chen, J. et al. Outcomes of congenital Zika disease depend on timing of infection and maternal-fetal interferon action. Cell Rep. 21, 1588–1599 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Singh, P. K., Singh, S., Farr, D. & Kumar, A. Interferon-stimulated gene 15 (ISG15) restricts Zika virus replication in primary human corneal epithelial cells. Ocul. Surf. 17, 551–559 (2019).

    PubMed  PubMed Central  Google Scholar 

  165. Forsberg, A., Abrahamsson, T. R., Björkstén, B. & Jenmalm, M. C. Pre- and post-natal Lactobacillus reuteri supplementation decreases allergen responsiveness in infancy. Clin. Exp. Allergy 43, 434–442 (2013).

    CAS  PubMed  Google Scholar 

  166. Karlsson, L. et al. Epigenetic alterations associated with early prenatal dexamethasone treatment. J. Endocr. Soc. 3, 250–263 (2019).

    CAS  PubMed  Google Scholar 

  167. Veru, F. et al. Prenatal maternal stress predicts reductions in CD4+ lymphocytes, increases in innate-derived cytokines, and a Th2 shift in adolescents: Project Ice Storm. Physiol. Behav. 144, 137–145 (2015).

    CAS  PubMed  Google Scholar 

  168. Yu, H. R. et al. Prenatal dexamethasone and postnatal high-fat diet decrease interferon gamma production through an age-dependent histone modification in male Sprague-Dawley Rats. Int. J. Mol. Sci. 17, 1610 (2016).

  169. Yu, H. R. et al. Prenatal dexamethasone exposure in rats results in long-term epigenetic histone modifications and tumour necrosis factor-α production decrease. Immunology 143, 651–660 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Kuo, C. H. et al. Early life exposure to antibiotics and the risk of childhood allergic diseases: an update from the perspective of the hygiene hypothesis. J. Microbiol. Immunol. Infect. 46, 320–329 (2013).

    CAS  PubMed  Google Scholar 

  171. Clarke, M. A. & Joshu, C. E. Early life exposures and adult cancer risk. Epidemiol. Rev. 39, 11–27 (2017).

    PubMed  PubMed Central  Google Scholar 

  172. McEniry, M., Palloni, A., Dávila, A. L. & Gurucharri, A. G. Early life exposure to poor nutrition and infectious diseases and its effects on the health of older Puerto Rican adults. J. Gerontol. B Psychol. Sci. Soc. Sci. 63, S337–348 (2008).

    PubMed  Google Scholar 

  173. Franz, M. B. et al. Global and single gene DNA methylation in umbilical cord blood cells after elective caesarean: a pilot study. Eur, J. Obstet. Gynecol. Reprod. Biol. 179, 121–124 (2014).

    CAS  Google Scholar 

  174. Schlinzig, T. et al. Epigenetic modulation at birth—altered DNA-methylation in white blood cells after Caesarean section. Acta Paediatr. 98, 1096–1099 (2009).

    CAS  PubMed  Google Scholar 

  175. Virani, S. et al. Delivery type not associated with global methylation at birth. Clin. Epigenetics 4, 8 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Oddy, W. H. Breastfeeding, childhood asthma, and allergic disease. Ann. Nutr. Metab. 70(Suppl. 2), 26–36 (2017).

    PubMed  Google Scholar 

  177. Horta, B. L., de Sousa, B. A. & de Mola, C. L. Breastfeeding and neurodevelopmental outcomes. Curr. Opin. Clin. Nutr. Metab. Care. 21, 174–178 (2018).

    PubMed  Google Scholar 

  178. Sherwood, W. B. et al. Epigenome-wide association study reveals duration of breastfeeding is associated with epigenetic differences in children. Int. J. Environ. Res. Public Health. 17, 3569 (2020).

  179. Alsaweed, M., Hartmann, P. E., Geddes, D. T. & Kakulas, F. MicroRNAs in breastmilk and the lactating breast: potential immunoprotectors and developmental regulators for the infant and the mother. Int. J. Environ. Res. Public Health 12, 13981–14020 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Carr, L. E. et al. Role of human milk bioactives on infants’ gut and immune health. Front. Immunol. 12, 604080 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Lind, M. V. et al. Genome-wide identification of mononuclear cell DNA methylation sites potentially affected by fish oil supplementation in young infants: a pilot study. Prostaglandins Leukot. Essent. Fat. Acids 101, 1–7 (2015).

    CAS  Google Scholar 

  182. Junge, K. M. et al. Increased vitamin D levels at birth and in early infancy increase offspring allergy risk-evidence for involvement of epigenetic mechanisms. J. Allergy Clin. Immunol. 137, 610–613 (2016).

    CAS  PubMed  Google Scholar 

  183. Zhu, H. et al. A genome-wide methylation study of severe vitamin D deficiency in African American adolescents. J. Pediatr. 162, 1004–1009. e1001 (2013) .

    CAS  PubMed  Google Scholar 

  184. Prendergast, A. J. Malnutrition and vaccination in developing countries. Philos. Trans. R. Soc. Lond. B Biol. Sci. 370, 20140141 (2015).

  185. Uchiyama, R. et al. Histone H3 lysine 4 methylation signature associated with human undernutrition. Proc. Natl Acad. Sci. USA 115, E11264–e11273 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Lorente-Pozo, S. et al. DNA methylation analysis to unravel altered genetic pathways underlying early onset and late onset neonatal sepsis. a pilot study. Front. Immunol. 12, 622599 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Bellos, I. et al. Soluble TREM-1 as a predictive factor of neonatal sepsis: a meta-analysis. Inflamm. Res. 67, 571–578 (2018).

    CAS  PubMed  Google Scholar 

  188. Patoulias, D., Kalogirou, M. S. & Patoulias, I. Triggering Receptor Expressed on Myeloid Cells-1 (TREM-1) and its soluble in the plasma form (sTREM-1) as a diagnostic biomarker in neonatal sepsis. Folia Med. Cracov. 58, 15–19 (2018).

    PubMed  Google Scholar 

  189. Heinemann, A. S. et al. In neonates S100A8/S100A9 alarmins prevent the expansion of a specific inflammatory monocyte population promoting septic shock. FASEB J. 31, 1153–1164 (2017).

    CAS  PubMed  Google Scholar 

  190. Cheng, Q., Tang, L. & Wang, Y. Regulatory role of miRNA-26a in neonatal sepsis. Exp. Ther. Med. 16, 4836–4842 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Dhas, B. B., Dirisala, V. R. & Bhat, B. V. Expression levels of candidate circulating microRNAs in early-onset neonatal sepsis compared with healthy newborns. Genomics Insights 11, 1178631018797079 (2018).

    PubMed  PubMed Central  Google Scholar 

  192. Chen, J., Jiang, S., Cao, Y. & Yang, Y. Altered miRNAs expression profiles and modulation of immune response genes and proteins during neonatal sepsis. J. Clin. Immunol. 34, 340–348 (2014).

    CAS  PubMed  Google Scholar 

  193. Wang, X. et al. miR-15a/16 are upreuglated in the serum of neonatal sepsis patients and inhibit the LPS-induced inflammatory pathway. Int. J. Clin. Exp. Med. 8, 5683–5690 (2015).

    PubMed  PubMed Central  Google Scholar 

  194. Mirzarahimi, M., Barak, M., Eslami, A. & Enteshari-Moghaddam, A. The role of interleukin-6 in the early diagnosis of sepsis in premature infants. Pediatr. Rep. 9, 7305 (2017).

    PubMed  PubMed Central  Google Scholar 

  195. Wu, P. & Hartert, T. V. Evidence for a causal relationship between respiratory syncytial virus infection and asthma. Expert Rev. Anti Infect. Ther. 9, 731–745 (2011).

    PubMed  PubMed Central  Google Scholar 

  196. Jackson, D. J. et al. Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. Am. J. Respir. Crit. Care Med. 178, 667–672 (2008).

    PubMed  PubMed Central  Google Scholar 

  197. Bergroth, E. et al. Rhinovirus type in severe bronchiolitis and the development of asthma. J. Allergy Clin. Immunol. Pract. 8, 588–595 (2020). e584.

    PubMed  Google Scholar 

  198. Elgizouli, M. et al. Cord blood PRF1 methylation patterns and risk of lower respiratory tract infections in infants: findings from the Ulm Birth Cohort. Medicine (Baltimore) 94, e332 (2015).

    CAS  Google Scholar 

  199. Elgizouli, M. et al. Reduced PRF1 enhancer methylation in children with a history of severe RSV bronchiolitis in infancy: an association study. BMC Pediatr. 17, 65 (2017).

    PubMed  PubMed Central  Google Scholar 

  200. Lund, R. J. et al. Atopic asthma after rhinovirus-induced wheezing is associated with DNA methylation change in the SMAD3 gene promoter. Allergy 73, 1735–1740 (2018).

    CAS  PubMed  Google Scholar 

  201. Pech, M. et al. Rhinovirus infections change DNA methylation and mRNA expression in children with asthma. PLoS ONE 13, e0205275 (2018).

    PubMed  PubMed Central  Google Scholar 

  202. Leahy, T. R. et al. Interleukin-15 is associated with disease severity in viral bronchiolitis. Eur. Respir. J. 47, 212–222 (2016).

    CAS  PubMed  Google Scholar 

  203. Inchley, C. S., Sonerud, T., Fjærli, H. O. & Nakstad, B. Nasal mucosal microRNA expression in children with respiratory syncytial virus infection. BMC Infect. Dis. 15, 150 (2015).

    PubMed  PubMed Central  Google Scholar 

  204. Zhang, X. et al. Identification of miRNA-mRNA crosstalk in respiratory syncytial virus- (RSV-) associated pediatric pneumonia through integrated miRNAome and transcriptome analysis. Mediators Inflamm. 2020, 8919534 (2020).

    PubMed  PubMed Central  Google Scholar 

  205. Wang, S. et al. Peripheral blood microRNAs expression is associated with infant respiratory syncytial virus infection. Oncotarget 8, 96627–96635 (2017).

    PubMed  PubMed Central  Google Scholar 

  206. Zhang, Y. & Shao, L. Decreased microRNA-140-5p contributes to respiratory syncytial virus disease through targeting Toll-like receptor 4. Exp. Ther. Med. 16, 993–999 (2018).

    PubMed  PubMed Central  Google Scholar 

  207. Liu, S., Gao, L., Wang, X. & Xing, Y. Respiratory syncytial virus infection inhibits TLR4 signaling via up-regulation of miR-26b. Cell Biol. Int. 39, 1376–1383 (2015).

    CAS  PubMed  Google Scholar 

  208. Arroyo, M. et al. Airway mir-155 responses are associated with TH1 cytokine polarization in young children with viral respiratory infections. PLoS ONE 15, e0233352 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. O’Connell, R. M., Rao, D. S., Chaudhuri, A. A. & Baltimore, D. Physiological and pathological roles for microRNAs in the immune system. Nat. Rev. Immunol. 10, 111–122 (2010).

    PubMed  Google Scholar 

  210. Gutierrez, M. J. et al. Airway secretory microRNAome changes during rhinovirus infection in early childhood. PLoS ONE 11, e0162244 (2016).

    PubMed  PubMed Central  Google Scholar 

  211. Hasegawa, K. et al. RSV vs. rhinovirus bronchiolitis: difference in nasal airway microRNA profiles and NFκB signaling. Pediatr. Res. 83, 606–614 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Winther, T. N. et al. Circulating MicroRNAs in plasma of hepatitis B e antigen positive children reveal liver-specific target genes. Int. J. Hepatol. 2014, 791045 (2014).

    PubMed  PubMed Central  Google Scholar 

  213. Winther, T. N. et al. Hepatitis B surface antigen quantity positively correlates with plasma levels of microRNAs differentially expressed in immunological phases of chronic hepatitis B in children. PLoS ONE 8, e80384 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Maruthai, K. et al. Assessment of global DNA methylation in children with tuberculosis disease. Int J. Mycobacteriol. 7, 338–342 (2018).

    CAS  PubMed  Google Scholar 

  215. Wang, J. X. et al. Diagnostic values of microRNA-31 in peripheral blood mononuclear cells for pediatric pulmonary tuberculosis in Chinese patients. Genet. Mol. Res. 14, 17235–17243 (2015).

    CAS  PubMed  Google Scholar 

  216. M, K., S, S. & S, M. Expression levels of candidate circulating microRNAs in pediatric tuberculosis. Pathog. Glob. Health 114, 262–270 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Malhotra, I. et al. Helminth- and Bacillus Calmette-Guérin-induced immunity in children sensitized in utero to filariasis and schistosomiasis. J. Immunol. 162, 6843–6848 (1999).

    CAS  PubMed  Google Scholar 

  218. Sabin, E. A., Araujo, M. I., Carvalho, E. M. & Pearce, E. J. Impairment of tetanus toxoid-specific Th1-like immune responses in humans infected with Schistosoma mansoni. J. Infect. Dis. 173, 269–272 (1996).

    CAS  PubMed  Google Scholar 

  219. DiNardo, A. R. et al. Schistosomiasis induces persistent DNA methylation and tuberculosis-specific immune changes. J. Immunol. 201, 124–133 (2018).

    CAS  PubMed  Google Scholar 

  220. Kohli, A. et al. Secondhand smoke in combination with ambient air pollution exposure is associated with increasedx CpG methylation and decreased expression of IFN-γ in T effector cells and Foxp3 in T regulatory cells in children. Clin. Epigenetics 4, 17 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Hew, K. M. et al. Childhood exposure to ambient polycyclic aromatic hydrocarbons is linked to epigenetic modifications and impaired systemic immunity in T cells. Clin. Exp. Allergy 45, 238–248 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Nadeau, K. et al. Ambient air pollution impairs regulatory T-cell function in asthma. J. Allergy Clin. Immunol. 126, 845–852 (2010). e810.

    CAS  PubMed  Google Scholar 

  223. Kobayashi, Y. et al. Passive smoking impairs histone deacetylase-2 in children with severe asthma. Chest 145, 305–312 (2014).

    CAS  PubMed  Google Scholar 

  224. Adler, N. E. & Stewart, J. Health disparities across the lifespan: meaning, methods, and mechanisms. Ann. N Y Acad. Sci. 1186, 5–23 (2010).

    PubMed  Google Scholar 

  225. Miller, G. E. et al. Low early-life social class leaves a biological residue manifested by decreased glucocorticoid and increased proinflammatory signaling. Proc. Natl Acad. Sci. USA 106, 14716–14721 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Bush, N. R. et al. The biological embedding of early-life socioeconomic status and family adversity in children’s genome-wide DNA methylation. Epigenomics 10, 1445–1461 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. Moosavi, A. & Motevalizadeh Ardekani, A. Role of epigenetics in biology and human diseases. Iran Biomed J 20, 246–258 (2016).

    PubMed  PubMed Central  Google Scholar 

  228. DeVries, A. & Vercelli, D. Epigenetic mechanisms in asthma. Ann Am Thorac Soc 13(Suppl. 1), S48–50 (2016).

    PubMed  PubMed Central  Google Scholar 

  229. Kellner, E. S. et al. The value of chromosome analysis to interrogate variants in DNMT3B causing immunodeficiency, centromeric instability, and facial anomaly syndrome Type I (ICF1). J. Clin. Immunol. 39, 857–859 (2019).

    PubMed  Google Scholar 

  230. Ehrlich, M. et al. ICF, an immunodeficiency syndrome: DNA methyltransferase 3B involvement, chromosome anomalies, and gene dysregulation. Autoimmunity 41, 253–271 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Stremenova Spegarova, J. et al. Germline TET2 loss of function causes childhood immunodeficiency and lymphoma. Blood 136, 1055–1066 (2020).

    PubMed  Google Scholar 

  232. Margot, H. et al. Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals. Genet. Med. 22, 181–188 (2020).

    PubMed  Google Scholar 

  233. Lin, J. L. et al. Immunologic assessment and KMT2D mutation detection in Kabuki syndrome. Clin. Genet. 88, 255–260 (2015).

    CAS  PubMed  Google Scholar 

  234. Caminati, M., Pham, D. L., Bagnasco, D. & Canonica, G. W. Type 2 immunity in asthma. World Allergy Organ. J. 11, 13 (2018).

    PubMed  PubMed Central  Google Scholar 

  235. Wynn, T. A. Type 2 cytokines: mechanisms and therapeutic strategies. Nat. Rev. Immunol. 15, 271–282 (2015).

    CAS  PubMed  Google Scholar 

  236. Zhao, S. T. & Wang, C. Z. Regulatory T cells and asthma. J. Zhejiang Univ. Sci. B 19, 663–673 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. DeVries, A. & Vercelli, D. Early predictors of asthma and allergy in children: the role of epigenetics. Curr. Opin. Allergy Clin. Immunol. 15, 435–439 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. Perry, M. M., Adcock, I. M. & Chung, K. F. Role of microRNAs in allergic asthma: present and future. Curr. Opin. Allergy Clin. Immunol. 15, 156–162 (2015).

    CAS  PubMed  Google Scholar 

  239. Liang, L. et al. An epigenome-wide association study of total serum immunoglobulin E concentration. Nature 520, 670–674 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  240. Everson, T. M. et al. DNA methylation loci associated with atopy and high serum IgE: a genome-wide application of recursive Random Forest feature selection. Genome Med. 7, 89 (2015).

    PubMed  PubMed Central  Google Scholar 

  241. Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, R115 (2013).

    PubMed  PubMed Central  Google Scholar 

  242. Peng, C. et al. Epigenetic age acceleration is associated with allergy and asthma in children in Project Viva. J. Allergy Clin. Immunol. 143, 2263–2270 (2019). e2214.

    PubMed  PubMed Central  Google Scholar 

  243. Wlasiuk, G. et al. Neonatal epigenetic predictors of childhood asthma map to immunoregulatory and pro-inflammatory pathways. B59. Asthma-Like Phenotype: Emergence of (Epi)Genetics and Targeted Transgenesis. Thematic Poster Session, A3524.

  244. DeVries, A. et al. Epigenome-wide analysis links SMAD3 methylation at birth to asthma in children of asthmatic mothers. J. Allergy Clin. Immunol. 140, 534–542 (2017).

    CAS  PubMed  Google Scholar 

  245. Reese, S. E. et al. Epigenome-wide meta-analysis of DNA methylation and childhood asthma. J. Allergy Clin. Immunol. 143, 2062–2074 (2019).

    CAS  PubMed  Google Scholar 

  246. Michel, S. et al. Farm exposure and time trends in early childhood may influence DNA methylation in genes related to asthma and allergy. Allergy 68, 355–364 (2013).

    CAS  PubMed  Google Scholar 

  247. Curtin, J. A. et al. Methylation of IL-2 promoter at birth alters the risk of asthma exacerbations during childhood. Clin. Exp. Allergy 43, 304–311 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  248. Yang, I. V. et al. DNA methylation and childhood asthma in the inner city. J. Allergy Clin. Immunol. 136, 69–80 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  249. Xu, C. J. et al. DNA methylation in childhood asthma: an epigenome-wide meta-analysis. Lancet Respir. Med. 6, 379–388 (2018).

    CAS  PubMed  Google Scholar 

  250. Runyon, R. S. et al. Asthma discordance in twins is linked to epigenetic modifications of T cells. PLoS ONE 7, e48796 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  251. Acevedo, N. et al. Risk of childhood asthma is associated with CpG-site polymorphisms, regional DNA methylation and mRNA levels at the GSDMB/ORMDL3 locus. Hum. Mol. Genet. 24, 875–890 (2015).

    CAS  PubMed  Google Scholar 

  252. Zhu, J., Cote-Sierra, J., Guo, L. & Paul, W. E. Stat5 activation plays a critical role in Th2 differentiation. Immunity 19, 739–748 (2003).

    CAS  PubMed  Google Scholar 

  253. Yang, I. V. et al. The nasal methylome and childhood atopic asthma. J. Allergy Clin. Immunol. 139, 1478–1488 (2017).

    CAS  PubMed  Google Scholar 

  254. Forno, E. et al. DNA methylation in nasal epithelium, atopy, and atopic asthma in children: a genome-wide study. Lancet Respir. Med. 7, 336–346 (2019).

    CAS  PubMed  Google Scholar 

  255. Kim, S. et al. Expression quantitative trait methylation analysis reveals methylomic associations with gene expression in childhood asthma. Chest 158, 1841–1856 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  256. Shi, K., Ge, M. N. & Chen, X. Q. Coordinated DNA methylation and gene expression data for identification of the critical genes associated with childhood atopic asthma. J. Comput. Biol. 27, 109–120 (2020).

    CAS  PubMed  Google Scholar 

  257. Breton, C. V. et al. DNA methylation in the arginase-nitric oxide synthase pathway is associated with exhaled nitric oxide in children with asthma. Am. J. Respir. Crit. Care Med. 184, 191–197 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  258. Lovinsky-Desir, S. et al. DNA methylation of the allergy regulatory gene interferon gamma varies by age, sex, and tissue type in asthmatics. Clin. Epigenetics 6, 9 (2014).

    PubMed  PubMed Central  Google Scholar 

  259. Hui, Y. et al. Efficacy analysis of three-year subcutaneous SQ-standardized specific immunotherapy in house dust mite-allergic children with asthma. Exp. Ther. Med. 7, 630–634 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  260. Wang, C. M. et al. Dust mite allergen-specific immunotherapy increases IL4 DNA methylation and induces Der p-specific T cell tolerance in children with allergic asthma. Cell. Mol. Immunol. 15, 963–972 (2018).

    CAS  PubMed  Google Scholar 

  261. Jiménez-Morales, S. et al. MiR-146a polymorphism is associated with asthma but not with systemic lupus erythematosus and juvenile rheumatoid arthritis in Mexican patients. Tissue Antigens 80, 317–321 (2012).

    PubMed  Google Scholar 

  262. Elnady, H. G. et al. Aberrant expression of immune-related MicroRNAs in pediatric patients with asthma. Int. J. Mol. Cell Med. 9, 246–255 (2020).

    CAS  PubMed  Google Scholar 

  263. Tian, M. et al. Changes in circulating microRNA-126 levels are associated with immune imbalance in children with acute asthma. Int. J. Immunopathol. Pharmacol. 32, 2058738418779243 (2018).

    PubMed  PubMed Central  Google Scholar 

  264. Hammad Mahmoud Hammad, R. et al. Plasma microRNA-21, microRNA-146a and IL-13 expression in asthmatic children. Innate Immun. 24, 171–179 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  265. Liu, F. et al. Profiling of miRNAs in pediatric asthma: upregulation of miRNA-221 and miRNA-485-3p. Mol. Med. Rep. 6, 1178–1182 (2012).

    CAS  PubMed  Google Scholar 

  266. Sawant, D. V. et al. Serum MicroRNA-21 as a biomarker for allergic inflammatory disease in children. MicroRNA 4, 36–40 (2015).

    PubMed  Google Scholar 

  267. Qin, H. B. et al. Inhibition of miRNA-221 suppresses the airway inflammation in asthma. Inflammation 35, 1595–1599 (2012).

    CAS  PubMed  Google Scholar 

  268. Dong, X. et al. Regulation of CBL and ESR1 expression by microRNA-22‑3p, 513a-5p and 625-5p may impact the pathogenesis of dust mite-induced pediatric asthma. Int. J. Mol. Med. 38, 446–456 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  269. Midyat, L. et al. MicroRNA expression profiling in children with different asthma phenotypes. Pediatr. Pulmonol. 51, 582–587 (2016).

    PubMed  Google Scholar 

  270. Harb, H. et al. Childhood allergic asthma is associated with increased IL-13 and FOXP3 histone acetylation. J. Allergy Clin. Immunol. 136, 200–202 (2015).

    CAS  PubMed  Google Scholar 

  271. Stefanowicz, D. et al. Elevated H3K18 acetylation in airway epithelial cells of asthmatic subjects. Respir. Res. 16, 95 (2015).

    PubMed  PubMed Central  Google Scholar 

  272. Puddicombe, S. M. et al. Involvement of the epidermal growth factor receptor in epithelial repair in asthma. FASEB J. 14, 1362–1374 (2000).

    CAS  PubMed  Google Scholar 

  273. Amishima, M. et al. Expression of epidermal growth factor and epidermal growth factor receptor immunoreactivity in the asthmatic human airway. Am. J. Respir. Crit. Care Med. 157, 1907–1912 (1998).

    CAS  PubMed  Google Scholar 

  274. Hackett, T. L. et al. Induction of epithelial-mesenchymal transition in primary airway epithelial cells from patients with asthma by transforming growth factor-beta1. Am. J. Respir. Crit. Care Med. 180, 122–133 (2009).

    CAS  PubMed  Google Scholar 

  275. Mullings, R. E. et al. Signal transducer and activator of transcription 6 (STAT-6) expression and function in asthmatic bronchial epithelium. J. Allergy Clin. Immunol. 108, 832–838 (2001).

    CAS  PubMed  Google Scholar 

  276. Tomita, K. et al. STAT6 expression in T cells, alveolar macrophages and bronchial biopsies of normal and asthmatic subjects. J. Inflamm. (Lond.) 9, 5 (2012).

    CAS  Google Scholar 

  277. Morin, A. et al. Epigenetic landscape links upper airway microbiota in infancy with allergic rhinitis at 6 years of age. J. Allergy Clin. Immunol. 146, 1358–1366 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  278. Qi, C. et al. Nasal DNA methylation profiling of asthma and rhinitis. J. Allergy Clin. Immunol. 145, 1655–1663 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  279. Rodríguez, E. et al. An integrated epigenetic and transcriptomic analysis reveals distinct tissue-specific patterns of DNA methylation associated with atopic dermatitis. J. Invest. Dermatol. 134, 1873–1883 (2014).

    PubMed  Google Scholar 

  280. Novak, N., Allam, P., Geiger, E. & Bieber, T. Characterization of monocyte subtypes in the allergic form of atopic eczema/dermatitis syndrome. Allergy 57, 931–935 (2002).

    CAS  PubMed  Google Scholar 

  281. Liang, Y. et al. Demethylation of the FCER1G promoter leads to FcεRI overexpression on monocytes of patients with atopic dermatitis. Allergy 67, 424–430 (2012).

    CAS  PubMed  Google Scholar 

  282. Luo, Y. et al. Promoter demethylation contributes to TSLP overexpression in skin lesions of patients with atopic dermatitis. Clin. Exp. Dermatol. 39, 48–53 (2014).

    CAS  PubMed  Google Scholar 

  283. Lv, Y. et al. Profiling of serum and urinary microRNAs in children with atopic dermatitis. PLoS ONE 9, e115448 (2014).

    PubMed  PubMed Central  Google Scholar 

  284. Sonkoly, E. et al. MiR-155 is overexpressed in patients with atopic dermatitis and modulates T-cell proliferative responses by targeting cytotoxic T lymphocyte-associated antigen 4. J. Allergy Clin. Immunol. 126, 581–589.e581–520 (2010).

    Google Scholar 

  285. Peng, C. et al. Epigenome-wide association study reveals methylation pathways associated with childhood allergic sensitization. Epigenetics 14, 445–466 (2019).

    PubMed  PubMed Central  Google Scholar 

  286. Martino, D. et al. Epigenome-wide association study reveals longitudinally stable DNA methylation differences in CD4+ T cells from children with IgE-mediated food allergy. Epigenetics 9, 998–1006 (2014).

    PubMed  PubMed Central  Google Scholar 

  287. Martino, D. et al. Epigenetic dysregulation of naive CD4+ T-cell activation genes in childhood food allergy. Nat. Commun. 9, 3308 (2018).

    PubMed  PubMed Central  Google Scholar 

  288. Hong, X. et al. Epigenome-wide association study links site-specific DNA methylation changes with cow’s milk allergy. J. Allergy Clin. Immunol. 138, 908–911 (2016). e909.

    CAS  PubMed  PubMed Central  Google Scholar 

  289. Berni Canani, R. et al. Differences in DNA methylation profile of Th1 and Th2 cytokine genes are associated with tolerance acquisition in children with IgE-mediated cow’s milk allergy. Clin. Epigenetics 7, 38 (2015).

    PubMed  PubMed Central  Google Scholar 

  290. Paparo, L. et al. Epigenetic features of FoxP3 in children with cow’s milk allergy. Clin. Epigenetics 8, 86 (2016).

    PubMed  PubMed Central  Google Scholar 

  291. Hong, X. et al. Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children. Nat. Commun. 6, 6304 (2015).

    CAS  PubMed  Google Scholar 

  292. Paparo, L. et al. Randomized controlled trial on the influence of dietary intervention on epigenetic mechanisms in children with cow’s milk allergy: the EPICMA study. Sci. Rep. 9, 2828 (2019).

    PubMed  PubMed Central  Google Scholar 

  293. Do, A. N. et al. Dual transcriptomic and epigenomic study of reaction severity in peanut-allergic children. J. Allergy Clin. Immunol. 145, 1219–1230 (2020).

    CAS  PubMed  Google Scholar 

  294. Martino, D. et al. Blood DNA methylation biomarkers predict clinical reactivity in food-sensitized infants. J. Allergy Clin. Immunol. 135, 1319–1328.e1311–1312 (2015).

    Google Scholar 

  295. Syed, A. et al. Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3). J. Allergy Clin. Immunol. 133, 500–510 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  296. Singer, K. & Lumeng, C. N. The initiation of metabolic inflammation in childhood obesity. J. Clin. Invest. 127, 65–73 (2017).

    PubMed  PubMed Central  Google Scholar 

  297. Rastogi, D., Suzuki, M. & Greally, J. M. Differential epigenome-wide DNA methylation patterns in childhood obesity-associated asthma. Sci. Rep. 3, 2164 (2013).

    PubMed  PubMed Central  Google Scholar 

  298. Li, Y. et al. Genome-wide analysis reveals that altered methylation in specific CpG loci is associated with childhood obesity. J. Cell. Biochem. 119, 7490–7497 (2018).

    CAS  PubMed  Google Scholar 

  299. Cao-Lei, L. et al. Differential genome-wide DNA methylation patterns in childhood obesity. BMC Res. Notes 12, 174 (2019).

    PubMed  PubMed Central  Google Scholar 

  300. Huang, R. C. et al. Genome-wide methylation analysis identifies differentially methylated CpG loci associated with severe obesity in childhood. Epigenetics 10, 995–1005 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  301. Rastogi, D. et al. Obesity-associated asthma in children: a distinct entity. Chest 141, 895–905 (2012).

    CAS  PubMed  Google Scholar 

  302. Khalyfa, A. et al. Circulating microRNAs as potential biomarkers of endothelial dysfunction in obese children. Chest 149, 786–800 (2016).

    PubMed  PubMed Central  Google Scholar 

  303. Minchenko, D. O. Insulin resistance in obese adolescents affects the expression of genes associated with immune response. Endocr. Regul. 53, 71–82 (2019).

    PubMed  Google Scholar 

  304. Carolan, E. et al. The impact of childhood obesity on inflammation, innate immune cell frequency, and metabolic microRNA expression. J. Clin. Endocrinol. Metab. 99, E474–E478 (2014).

    CAS  PubMed  Google Scholar 

  305. Lee, S. H., Kwon, J. E. & Cho, M. L. Immunological pathogenesis of inflammatory bowel disease. Intest. Res. 16, 26–42 (2018).

    PubMed  PubMed Central  Google Scholar 

  306. Harris, R. A. et al. DNA methylation-associated colonic mucosal immune and defense responses in treatment-naïve pediatric ulcerative colitis. Epigenetics 9, 1131–1137 (2014).

    PubMed  PubMed Central  Google Scholar 

  307. Béres, N. J. et al. Altered mucosal expression of microRNAs in pediatric patients with inflammatory bowel disease. Dig. Liver Dis. 49, 378–387 (2017).

    PubMed  Google Scholar 

  308. Koukos, G. et al. MicroRNA-124 regulates STAT3 expression and is down-regulated in colon tissues of pediatric patients with ulcerative colitis. Gastroenterology 145, 842–852 (2013). e842.

    CAS  PubMed  Google Scholar 

  309. Koukos, G. et al. A microRNA signature in pediatric ulcerative colitis: deregulation of the miR-4284/CXCL5 pathway in the intestinal epithelium. Inflamm. Bowel Dis. 21, 996–1005 (2015).

    PubMed  Google Scholar 

  310. Zahm, A. M. et al. Rectal microRNAs are perturbed in pediatric inflammatory bowel disease of the colon. J. Crohns Colitis 8, 1108–1117 (2014).

    PubMed  Google Scholar 

  311. Béres, N. J. et al. Role of altered expression of miR-146a, miR-155, and miR-122 in pediatric patients with inflammatory bowel disease. Inflamm. Bowel Dis. 22, 327–335 (2016).

    PubMed  Google Scholar 

  312. Szűcs, D. et al. Increased duodenal expression of miR-146a and -155 in pediatric Crohn’s disease. World J. Gastroenterol. 22, 6027–6035 (2016).

    PubMed  PubMed Central  Google Scholar 

  313. Tang, W. J. et al. MicroRNA-15a - cell division cycle 42 signaling pathway in pathogenesis of pediatric inflammatory bowel disease. World J. Gastroenterol. 24, 5234–5245 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  314. Zahm, A. M. et al. Circulating microRNA is a biomarker of pediatric Crohn disease. J. Pediatr. Gastroenterol. Nutr. 53, 26–33 (2011).

    CAS  PubMed  Google Scholar 

  315. Heier, C. R. et al. Identification of pathway-specific serum biomarkers of response to glucocorticoid and infliximab treatment in children with inflammatory bowel disease. Clin. Transl. Gastroenterol. 7, e192 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  316. De Iudicibus, S. et al. High-throughput sequencing of microRNAs in glucocorticoid sensitive paediatric inflammatory bowel disease patients. Int. J. Mol. Sci. 19, 1399 (2018).

  317. Caio, G. et al. Celiac disease: a comprehensive current review. BMC Med. 17, 142 (2019).

    PubMed  PubMed Central  Google Scholar 

  318. Amr, K. S., Bayoumi, F. S., Eissa, E. & Abu-Zekry, M. Circulating microRNAs as potential non-invasive biomarkers in pediatric patients with celiac disease. Eur. Ann. Allergy Clin. Immunol. 51, 159–164 (2019).

    CAS  PubMed  Google Scholar 

  319. Haberman, Y. et al. Mucosal genomics implicate lymphocyte activation and lipid metabolism in refractory environmental enteric dysfunction. Gastroenterology 160, 2055–2071 (2021).

  320. Xiao, Y. T. et al. Downregulated expression of microRNA-124 in pediatric intestinal failure patients modulates macrophages activation by inhibiting STAT3 and AChE. Cell Death Dis. 7, e2521 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  321. Lakshminarayanan, B. & Davenport, M. Biliary atresia: a comprehensive review. J. Autoimmun. 73, 1–9 (2016).

    PubMed  Google Scholar 

  322. Li, K. et al. Foxp3 promoter methylation impairs suppressive function of regulatory T cells in biliary atresia. Am. J. Physiol. Gastrointest. Liver Physiol. 311, G989–g997 (2016).

    PubMed  Google Scholar 

  323. Zhao, R. et al. MicroRNA-155 modulates bile duct inflammation by targeting the suppressor of cytokine signaling 1 in biliary atresia. Pediatr. Res. 82, 1007–1016 (2017).

    CAS  PubMed  Google Scholar 

  324. Smith, M. et al. Using next-generation sequencing of microRNAs to identify host and/or pathogen nucleic acid signatures in samples from children with biliary atresia—a pilot study. Access Microbiol. 2, acmi000127 (2020).

    PubMed  PubMed Central  Google Scholar 

  325. Katsarou, A. et al. Type 1 diabetes mellitus. Nat. Rev. Dis. Prim. 3, 17016 (2017).

    PubMed  Google Scholar 

  326. Stefan, M. et al. DNA methylation profiles in type 1 diabetes twins point to strong epigenetic effects on etiology. J. Autoimmun. 50, 33–37 (2014).

    CAS  PubMed  Google Scholar 

  327. Paul, D. S. et al. Increased DNA methylation variability in type 1 diabetes across three immune effector cell types. Nat. Commun. 7, 13555 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  328. Zhang, Y. et al. MicroRNAs in CD4(+) T cell subsets are markers of disease risk and T cell dysfunction in individuals at risk for type 1 diabetes. J. Autoimmun. 68, 52–61 (2016).

    CAS  PubMed  Google Scholar 

  329. Marchand, L. et al. miRNA-375 a sensor of glucotoxicity is altered in the serum of children with newly diagnosed Type 1 diabetes. J. Diabetes Res. 2016, 1869082 (2016).

    PubMed  PubMed Central  Google Scholar 

  330. Nielsen, L. B. et al. Circulating levels of microRNA from children with newly diagnosed type 1 diabetes and healthy controls: evidence that miR-25 associates to residual beta-cell function and glycaemic control during disease progression. Exp. Diabetes Res. 2012, 896362 (2012).

    PubMed  PubMed Central  Google Scholar 

  331. Zurawek, M. et al. miR-487a-3p upregulated in type 1 diabetes targets CTLA4 and FOXO3. Diabetes Res. Clin. Pract. 142, 146–153 (2018).

    CAS  PubMed  Google Scholar 

  332. Tesovnik, T. et al. Extracellular vesicles derived human-miRNAs modulate the immune system in Type 1 diabetes. Front. Cell Dev. Biol. 8, 202 (2020).

    PubMed  PubMed Central  Google Scholar 

  333. Garavelli, S. et al. Plasma circulating miR-23~27~24 clusters correlate with the immunometabolic derangement and predict C-peptide loss in children with type 1 diabetes. Diabetologia 63, 2699–2712 (2020).

    CAS  PubMed  Google Scholar 

  334. Samandari, N. et al. Influence of disease duration on circulating levels of miRNAs in children and adolescents with new onset Type 1 diabetes. Noncoding RNA 4, 35 (2018).

  335. Osipova, J. et al. Diabetes-associated microRNAs in pediatric patients with type 1 diabetes mellitus: a cross-sectional cohort study. J. Clin. Endocrinol. Metab. 99, E1661–1665 (2014).

    CAS  PubMed  Google Scholar 

  336. Małachowska, B. et al. Temporal dynamics of serum let-7g expression mirror the decline of residual beta-cell function in longitudinal observation of children with type 1 diabetes. Pediatr. Diabetes 19, 1407–1415 (2018).

    PubMed  Google Scholar 

  337. Barut, K., Adrovic, A., Şahin, S. & Kasapçopur, Ö. Juvenile idiopathic arthritis. Balk. Med J. 34, 90–101 (2017).

    Google Scholar 

  338. Ghavidel, A. A., Shiari, R., Hassan-Zadeh, V. & Farivar, S. The expression of DNMTs is dramatically decreased in peripheral blood mononuclear cells of male patients with juvenile idiopathic arthritis. Allergol. Immunopathol. (Madr.). 48, 182–186 (2020).

    PubMed  Google Scholar 

  339. Demir, F., Çebi, A. H. & Kalyoncu, M. Evaluation of plasma microRNA expressions in patients with juvenile idiopathic arthritis. Clin. Rheumatol. 37, 3255–3262 (2018).

    PubMed  Google Scholar 

  340. Lashine, Y. A., Salah, S., Aboelenein, H. R. & Abdelaziz, A. I. Correcting the expression of miRNA-155 represses PP2Ac and enhances the release of IL-2 in PBMCs of juvenile SLE patients. Lupus 24, 240–247 (2015).

    CAS  PubMed  Google Scholar 

  341. Yeung, K. S. et al. Cell lineage-specific genome-wide DNA methylation analysis of patients with paediatric-onset systemic lupus erythematosus. Epigenetics 14, 341–351 (2019).

    PubMed  PubMed Central  Google Scholar 

  342. Hanaei, S. et al. The status of FOXP3 gene methylation in pediatric systemic lupus erythematosus. Allergol. Immunopathol. (Madr.). 48, 332–338 (2020).

    CAS  PubMed  Google Scholar 

  343. Lashine, Y. A., Seoudi, A. M., Salah, S. & Abdelaziz, A. I. Expression signature of microRNA-181-a reveals its crucial role in the pathogenesis of paediatric systemic lupus erythematosus. Clin. Exp. Rheumatol. 29, 351–357 (2011).

    CAS  PubMed  Google Scholar 

  344. Reamy, B. V., Servey, J. T. & Williams, P. M. Henoch-Schönlein Purpura (IgA Vasculitis): rapid evidence review. Am. Fam. Physician 102, 229–233 (2020).

    PubMed  Google Scholar 

  345. Cebi, A. H., Demir, F., Ikbal, M. & Kalyoncu, M. Plasma microRNA levels in childhood IgA vasculitis. Clin. Rheumatol. 40, 1975–1981 (2020).

  346. Ramphul, K. & Mejias, S. G. Kawasaki disease: a comprehensive review. Arch. Med Sci. Atheroscler. Dis. 3, e41–e45 (2018).

    PubMed  PubMed Central  Google Scholar 

  347. Chang, D., Qian, C., Li, H. & Feng, H. Comprehensive analyses of DNA methylation and gene expression profiles of Kawasaki disease. J. Cell. Biochem. 120, 13001–13011 (2019).

    CAS  PubMed  Google Scholar 

  348. Huang, Y. H. et al. HAMP promoter hypomethylation and increased hepcidin levels as biomarkers for Kawasaki disease. J. Mol. Cell. Cardiol. 117, 82–87 (2018).

    CAS  PubMed  Google Scholar 

  349. Kuo, H. C. et al. Identification of an association between genomic hypomethylation of FCGR2A and susceptibility to Kawasaki disease and intravenous immunoglobulin resistance by DNA methylation array. Arthritis Rheumatol. 67, 828–836 (2015).

    CAS  PubMed  Google Scholar 

  350. Huang, Y. H. et al. Increase expression of CD177 in Kawasaki disease. Pediatr. Rheumatol. Online J. 17, 13 (2019).

    PubMed  PubMed Central  Google Scholar 

  351. Kuo, H. C., Li, S. C., Huang, L. H. & Huang, Y. H. Epigenetic hypomethylation and upregulation of matrix metalloproteinase 9 in Kawasaki disease. Oncotarget 8, 60875–60891 (2017).

    PubMed  PubMed Central  Google Scholar 

  352. Huang, Y. H. et al. Identifying genetic hypomethylation and upregulation of Toll-like receptors in Kawasaki disease. Oncotarget 8, 11249–11258 (2017).

    PubMed  PubMed Central  Google Scholar 

  353. Li, S. C. et al. Major methylation alterations on the CpG markers of inflammatory immune associated genes after IVIG treatment in Kawasaki disease. BMC Med. Genomics 9(Suppl. 1), 37 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  354. Yun, K. W. et al. Elevated serum level of microRNA (miRNA)-200c and miRNA-371-5p in children with Kawasaki disease. Pediatr. Cardiol. 35, 745–752 (2014).

    PubMed  Google Scholar 

  355. Ni, F. F. et al. Regulatory T cell microRNA expression changes in children with acute Kawasaki disease. Clin. Exp. Immunol. 178, 384–393 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  356. Rodeghiero, F. et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 113, 2386–2393 (2009).

    CAS  PubMed  Google Scholar 

  357. Gouda, H. M., Kamel, N. M. & Meshaal, S. S. Association of DNA methyltransferase 3B promotor polymorphism with childhood chronic immune thrombocytopenia. Lab. Med. 47, 312–317 (2016).

    PubMed  Google Scholar 

  358. Chen, Z. et al. Foxp3 methylation status in children with primary immune thrombocytopenia. Hum. Immunol. 75, 1115–1119 (2014).

    CAS  PubMed  Google Scholar 

  359. Bay, A. et al. Plasma microRNA profiling of pediatric patients with immune thrombocytopenic purpura. Blood Coagul. Fibrinolysis 25, 379–383 (2014).

    CAS  PubMed  Google Scholar 

  360. Goetz, D. & Ren, C. L. Review of cystic fibrosis. Pediatr. Ann. 48, e154–e161 (2019).

    PubMed  Google Scholar 

  361. Stachowiak, Z. et al. MiRNA expression profile in the airways is altered during pulmonary exacerbation in children with cystic fibrosis—a preliminary report. J. Clin. Med. 9, 1887 (2020).

  362. Krause, K. et al. The expression of Mirc1/Mir17-92 cluster in sputum samples correlates with pulmonary exacerbations in cystic fibrosis patients. J. Cyst. Fibrosis 17, 454–461 (2018).

    CAS  Google Scholar 

  363. Thébaud, B. et al. Bronchopulmonary dysplasia. Nat. Rev. Dis. Prim. 5, 78 (2019).

    PubMed  Google Scholar 

  364. Cuna, A. et al. Alterations in gene expression and DNA methylation during murine and human lung alveolar septation. Am. J. Respir. Cell Mol. Biol. 53, 60–73 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  365. Schiavinato, J., et al. TGF-beta/atRA-inducedTregs express a selected set of microRNAsinvolved in the repression of transcripts relatedto Th17 differentiation. Sci. Rep. 7, 3627 (2017).

Download references

Acknowledgements

This study received no financial support and has no financial ties to anything referenced in the manuscript.

Author information

Authors and Affiliations

Authors

Contributions

Drafting the article or revising it critically for important intellectual content: J.B., M.S. Final approval of the version to be published: J.B., M.S.

Corresponding author

Correspondence to Jennifer Bermick.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bermick, J., Schaller, M. Epigenetic regulation of pediatric and neonatal immune responses. Pediatr Res 91, 297–327 (2022). https://doi.org/10.1038/s41390-021-01630-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41390-021-01630-3

Further reading

Search

Quick links