Mammalian sperm RNA is increasingly recognized as an additional source of paternal hereditary information beyond DNA. Environmental inputs, including an unhealthy diet, mental stresses and toxin exposure, can reshape the sperm RNA signature and induce offspring phenotypes that relate to paternal environmental stressors. Our understanding of the categories of sperm RNAs (such as tRNA-derived small RNAs, microRNAs, ribosomal RNA-derived small RNAs and long non-coding RNAs) and associated RNA modifications is expanding and has begun to reveal the functional diversity and information capacity of these molecules. However, the coding mechanism endowed by sperm RNA structures and by RNA interactions with DNA and other epigenetic factors remains unknown. How sperm RNA-encoded information is decoded in early embryos to control offspring phenotypes also remains unclear. Complete deciphering of the ‘sperm RNA code’ with regard to metabolic control could move the field towards translational applications and precision medicine, and this may lead to prevention of intergenerational transmission of obesity and type 2 diabetes mellitus susceptibility.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $17.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Barres, R. & Zierath, J. R. The role of diet and exercise in the transgenerational epigenetic landscape of T2DM. Nat. Rev. Endocrinol. 12, 441–451 (2016).
Sales, V. M., Ferguson-Smith, A. C. & Patti, M. E. Epigenetic mechanisms of transmission of metabolic disease across generations. Cell Metab. 25, 559–571 (2017).
Fleming, T. P. et al. Origins of lifetime health around the time of conception: causes and consequences. Lancet 391, 1842–1852 (2018).
Eichler, E. E. et al. Missing heritability and strategies for finding the underlying causes of complex disease. Nat. Rev. Genet. 11, 446–450 (2010).
Skvortsova, K., Iovino, N. & Bogdanovic, O. Functions and mechanisms of epigenetic inheritance in animals. Nat. Rev. Mol. Cell Biol. 19, 774–790 (2018).
Miska, E. A. & Ferguson-Smith, A. C. Transgenerational inheritance: models and mechanisms of non-DNA sequence-based inheritance. Science 354, 59–63 (2016).
Heard, E. & Martienssen, R. A. Transgenerational epigenetic inheritance: myths and mechanisms. Cell 157, 95–109 (2014).
Chen, Q., Yan, W. & Duan, E. Epigenetic inheritance of acquired traits through sperm RNAs and sperm RNA modifications. Nat. Rev. Genet. 17, 733–743 (2016).
Perez, M. F. & Lehner, B. Intergenerational and transgenerational epigenetic inheritance in animals. Nat. Cell Biol. 21, 143–151 (2019).
Bouret, S., Levin, B. E. & Ozanne, S. E. Gene-environment interactions controlling energy and glucose homeostasis and the developmental origins of obesity. Physiol. Rev. 95, 47–82 (2015).
Oestreich, A. K. & Moley, K. H. Developmental and transmittable origins of obesity-associated health disorders. Trends Genet. 33, 399–407 (2017).
Godfrey, K. M. et al. Influence of maternal obesity on the long-term health of offspring. Lancet Diabetes Endocrinol. 5, 53–64 (2017).
Radford, E. J. et al. In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science 345, 1255903 (2014).
Kazachenka, A. et al. Identification, characterization, and heritability of murine metastable epialleles: implications for non-genetic inheritance. Cell 175, 1259–1271 (2018).
Hammoud, S. S. et al. Distinctive chromatin in human sperm packages genes for embryo development. Nature 460, 473–478 (2009).
Brykczynska, U. et al. Repressive and active histone methylation mark distinct promoters in human and mouse spermatozoa. Nat. Struct. Mol. Biol. 17, 679–687 (2010).
Siklenka, K. et al. Disruption of histone methylation in developing sperm impairs offspring health transgenerationally. Science 350, aab2006 (2015).
Chen, Q. et al. Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science 351, 397–400 (2016).
Gapp, K. et al. Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma. Mol. Psychiatry. https://doi.org/10.1038/s41380-018-0271-6 (2018).
Grandjean, V. et al. RNA-mediated paternal heredity of diet-induced obesity and metabolic disorders. Sci. Rep. 5, 18193 (2015).
Gapp, K. et al. Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat. Neurosci. 17, 667–669 (2014).
Zhang, Y. et al. Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs. Nat. Cell Biol. 20, 535–540 (2018).
Johnson, G. D. et al. Chromatin and extracellular vesicle associated sperm RNAs. Nucleic Acids Res. 43, 6847–6859 (2015).
Peng, H. et al. A novel class of tRNA-derived small RNAs extremely enriched in mature mouse sperm. Cell Res. 22, 1609–1612 (2012).
Sharma, U. et al. Small RNAs are trafficked from the epididymis to developing mammalian sperm. Dev. Cell 46, 481–494 (2018).
Sharma, U. et al. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 351, 391–396 (2016).
Chu, C. et al. A sequence of 28S rRNA-derived small RNAs is enriched in mature sperm and various somatic tissues and possibly associates with inflammation. J. Mol. Cell Biol. 9, 256–259 (2017).
Shi, J. et al. SPORTS1.0: a tool for annotating and profiling non-coding RNAs optimized for rRNA- and tRNA-derived small RNAs. Genomics Proteomics Bioinformatics 16, 144–151 (2018).
Schuster, A. et al. SpermBase: a database for sperm-borne RNA contents. Biol. Reprod. 95, 99 (2016).
Hua, M. et al. Identification of small non-coding RNAs as sperm quality biomarkers for in vitro fertilization. Cell Discov. 5, 20 (2019).
Schimmel, P. The emerging complexity of the tRNA world: mammalian tRNAs beyond protein synthesis. Nat. Rev. Mol. Cell Biol. 19, 45–58 (2018).
Guo, L. et al. Sperm-carried RNAs play critical roles in mouse embryonic development. Oncotarget 8, 67394–67405 (2017).
Yuan, S. et al. Sperm-borne miRNAs and endo-siRNAs are important for fertilization and preimplantation embryonic development. Development 143, 635–647 (2016).
Frye, M. et al. RNA modifications modulate gene expression during development. Science 361, 1346–1349 (2018).
Pan, T. Modifications and functional genomics of human transfer RNA. Cell Res. 28, 395–404 (2018).
Guzzi, N. et al. Pseudouridylation of tRNA-derived fragments steers translational control in stem cells. Cell 173, 1204–1216 (2018).
Safra, M. et al. The m1A landscape on cytosolic and mitochondrial mRNA at single-base resolution. Nature 551, 251–255 (2017).
Murashov, A. K. et al. Paternal long-term exercise programs offspring for low energy expenditure and increased risk for obesity in mice. FASEB J. 30, 775–784 (2016).
Rompala, G. R. et al. Heavy chronic intermittent ethanol exposure alters small noncoding RNAs in mouse sperm and epididymosomes. Front. Genet. 9, 32 (2018).
Rassoulzadegan, M. et al. RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse. Nature 441, 469–474 (2006).
Kiani, J. et al. RNA-mediated epigenetic heredity requires the cytosine methyltransferase Dnmt2. PLoS Genet. 9, e1003498 (2013).
Schulz, N. K. E., Diddens-de Buhr, M. F. & Kurtz, J. Paternal knockdown of Dnmt2 increases offspring susceptibility to bacterial infection. Preprint at bioRxiv https://www.biorxiv.org/content/10.1101/422063v1 (2018).
Lyko, F. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat. Rev. Genet. 19, 81–92 (2018).
Zhang, X. et al. Small RNA modifications: integral to function and disease. Trends Mol. Med. 22, 1025–1034 (2016).
Schaefer, M. et al. RNA methylation by Dnmt2 protects transfer RNAs against stress-induced cleavage. Genes Dev. 24, 1590–1595 (2010).
Tuorto, F. et al. RNA cytosine methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis. Nat. Struct. Mol. Biol. 19, 900–905 (2012).
Legrand, C. et al. Statistically robust methylation calling for whole-transcriptome bisulfite sequencing reveals distinct methylation patterns for mouse RNAs. Genome Res. 27, 1589–1596 (2017).
Tuorto, F. et al. Queuosine-modified tRNAs confer nutritional control of protein translation. EMBO J. 37, e99777 (2018).
Muller, M. et al. Dynamic modulation of Dnmt2-dependent tRNA methylation by the micronutrient queuine. Nucleic Acids Res. 43, 10952–10962 (2015).
Wang, X. et al. Queuosine modification protects cognate tRNAs against ribonuclease cleavage. RNA 24, 1305–1313 (2018).
Shi, J. et al. tsRNAs: the Swiss army knife for translational regulation. Trends Biochem. Sci. 44, 185–189 (2018).
Wang, X. et al. Transcriptome-wide reprogramming of N(6)-methyladenosine modification by the mouse microbiome. Cell Res. 29, 167–170 (2019).
Nelson, V. R. et al. Transgenerational epigenetic effects of the Apobec1 cytidine deaminase deficiency on testicular germ cell tumor susceptibility and embryonic viability. Proc. Natl Acad. Sci. U. S. A. 109, E2766–E2773 (2012).
Liu, W. M. et al. Sperm-borne microRNA-34c is required for the first cleavage division in mouse. Proc. Natl Acad. Sci. U. S. A. 109, 490–494 (2012).
Yuan, S. et al. mir-34b/c and mir-449a/b/c are required for spermatogenesis, but not for the first cleavage division in mice. Biol. Open 4, 212–223 (2015).
Conine, C. C. et al. Small RNAs gained during epididymal transit of sperm are essential for embryonic development in mice. Dev. Cell 46, 470–480 (2018).
Suganuma, R., Yanagimachi, R. & Meistrich, M. L. Decline in fertility of mouse sperm with abnormal chromatin during epididymal passage as revealed by ICSI. Hum. Reprod. 20, 3101–3108 (2005).
Cheng, H. S. et al. Increased susceptibility of post-weaning rats on high-fat diet to metabolic syndrome. J. Adv. Res. 8, 743–752 (2017).
Sarker, G. et al. Maternal overnutrition programs hedonic and metabolic phenotypes across generations through sperm tsRNAs. Proc. Natl Acad. Sci. U. S. A. 116, 10547–10556 (2019).
Rechavi, O. & Lev, I. Principles of transgenerational small RNA inheritance in Caenorhabditis elegans. Curr. Biol. 27, R720–R730 (2017).
Yu, R., Wang, X. & Moazed, D. Epigenetic inheritance mediated by coupling of RNAi and histone H3K9 methylation. Nature 558, 615–619 (2018).
Motamedi, M. R. et al. Two RNAi complexes, RITS and RDRC, physically interact and localize to noncoding centromeric RNAs. Cell 119, 789–802 (2004).
Ost, A. et al. Paternal diet defines offspring chromatin state and intergenerational obesity. Cell 159, 1352–1364 (2014).
Daxinger, L. et al. Hypomethylation of ERVs in the sperm of mice haploinsufficient for the histone methyltransferase Setdb1 correlates with a paternal effect on phenotype. Sci. Rep. 6, 25004 (2016).
Morgan, H. D. et al. Epigenetic inheritance at the agouti locus in the mouse. Nat. Genet. 23, 314–318 (1999).
Schorn, A. J. et al. LTR-retrotransposon control by tRNA-derived small RNAs. Cell 170, 61–71 (2017).
Genenncher, B. et al. Mutations in cytosine-5 tRNA methyltransferases impact mobile element expression and genome stability at specific DNA repeats. Cell Rep. 22, 1861–1874 (2018).
Martinez, G. tRNA-derived small RNAs: new players in genome protection against retrotransposons. RNA Biol. 15, 170–175 (2018).
Zhang, Y., Shi, J. & Chen, Q. tsRNAs: new players in mammalian retrotransposon control. Cell Res. 27, 1307–1308 (2017).
Schorn, A. J. & Martienssen, R. Tie-break: host and retrotransposons play tRNA. Trends Cell Biol. 28, 793–806 (2018).
Horie, M. et al. An RNA-dependent RNA polymerase gene in bat genomes derived from an ancient negative-strand RNA virus. Sci. Rep. 6, 25873 (2016).
Yang, Q. et al. Highly sensitive sequencing reveals dynamic modifications and activities of small RNAs in mouse oocytes and early embryos. Sci. Adv. 2, e1501482 (2016).
Zhang, B. et al. Allelic reprogramming of the histone modification H3K4me3 in early mammalian development. Nature 537, 553–557 (2016).
Dahl, J. A. et al. Broad histone H3K4me3 domains in mouse oocytes modulate maternal-to-zygotic transition. Nature 537, 548–552 (2016).
van de Werken, C. et al. Paternal heterochromatin formation in human embryos is H3K9/HP1 directed and primed by sperm-derived histone modifications. Nat. Commun. 5, 5868 (2014).
Genuth, N. R. & Barna, M. The discovery of ribosome heterogeneity and its implications for gene regulation and organismal life. Mol. Cell 71, 364–374 (2018).
Shi, Z. et al. Heterogeneous ribosomes preferentially translate distinct subpools of mRNAs genome-wide. Mol. Cell 67, 71–83 (2017).
Li, X. et al. Regulation of chromatin and gene expression by metabolic enzymes and metabolites. Nat. Rev. Mol. Cell Biol. 19, 563–578 (2018).
Chen, Q. et al. Tracing the origin of heterogeneity and symmetry breaking in the early mammalian embryo. Nat. Commun. 9, 1819 (2018).
Shi, J. et al. Dynamic transcriptional symmetry-breaking in pre-implantation mammalian embryo development revealed by single-cell RNA-seq. Development 142, 3468–3477 (2015).
Skinner, M. K. et al. Alterations in sperm DNA methylation, non-coding RNA and histone retention associate with DDT-induced epigenetic transgenerational inheritance of disease. Epigenetics Chromatin 11, 8 (2018).
Schuster, A., Skinner, M. K. & Yan, W. Ancestral vinclozolin exposure alters the epigenetic transgenerational inheritance of sperm small noncoding RNAs. Environ. Epigenet. 2, dvw001 (2016).
Donkin, I. et al. Obesity and bariatric surgery drive epigenetic variation of spermatozoa in humans. Cell Metab. 23, 369–378 (2016).
Stanford, K. I. et al. Paternal exercise improves glucose metabolism in adult offspring. Diabetes 67, 2530–2540 (2018).
Ingerslev, L. R. et al. Endurance training remodels sperm-borne small RNA expression and methylation at neurological gene hotspots. Clin. Epigenet. 10, 12 (2018).
Kwok, C. K. et al. rG4-seq reveals widespread formation of G-quadruplex structures in the human transcriptome. Nat. Methods 13, 841–844 (2016).
Goodwin, S., McPherson, J. D. & McCombie, W. R. Coming of age: ten years of next-generation sequencing technologies. Nat. Rev. Genet. 17, 333–351 (2016).
Zhang, Y. & Chen, Q. The expanding repertoire of hereditary information carriers. Development 146, dev170902 (2019).
Dekker, J. et al. The 4D nucleome project. Nature 549, 219–226 (2017).
Guo, F. et al. Single-cell multi-omics sequencing of mouse early embryos and embryonic stem cells. Cell Res. 27, 967–988 (2017).
Bian, S. et al. Single-cell multiomics sequencing and analyses of human colorectal cancer. Science 362, 1060–1063 (2018).
Li, X. et al. GRID-seq reveals the global RNA-chromatin interactome. Nat. Biotechnol. 35, 940–950 (2017).
Lu, Z. et al. RNA duplex map in living cells reveals higher-order transcriptome structure. Cell 165, 1267–1279 (2016).
Topol, E. J. High-performance medicine: the convergence of human and artificial intelligence. Nat. Med. 25, 44–56 (2019).
Rodriguez, K. F. et al. Effects of in utero exposure to arsenic during the second half of gestation on reproductive end points and metabolic parameters in female CD-1 mice. Environ. Health Perspect. 124, 336–343 (2016).
Dias, B. G. & Ressler, K. J. Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat. Neurosci. 17, 89–96 (2014).
Sun, W. et al. Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring. Nat. Med. 24, 1372–1383 (2018).
Le, Q. et al. Drug-seeking motivation level in male rats determines offspring susceptibility or resistance to cocaine-seeking behaviour. Nat. Commun. 8, 15527 (2017).
Yan, W. et al. Birth of mice after intracytoplasmic injection of single purified sperm nuclei and detection of messenger RNAs and MicroRNAs in the sperm nuclei. Biol. Reprod. 78, 896–902 (2008).
Lalancette, C. et al. Paternal contributions: new functional insights for spermatozoal RNA. J. Cell. Biochem. 104, 1570–1579 (2008).
Hamatani, T. Human spermatozoal RNAs. Fertil. Steril. 97, 275–281 (2012).
Al-Dossary, A. A. et al. Oviductosome-sperm membrane interaction in cargo delivery: detection of fusion and underlying molecular players using three-dimensional super-resolution structured illumination microscopy (SR-SIM). J. Biol. Chem. 290, 17710–17723 (2015).
Liu, Y. & Chen, Q. 150 years of Darwin’s theory of intercellular flow of hereditary information. Nat. Rev. Mol. Cell Biol. 19, 749–750 (2018).
The authors thank members of the Chen laboratory for extensive discussions on the manuscript. Y.Z. is supported by the Army Medical University (18JS008 and 2018XLC2018). F.T. is supported by the Institute of Genetics and Biophysics A. Buzzati-Traverso, C.N.R., Italy. M.R. is supported by La Fondation Nestlé France. Research in the Q.C. laboratory is supported by the NIH (R01HD092431).
Nature Reviews Endocrinology thanks R. Barrès, M.-E. Patti and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Seminars in Cell & Developmental Biology (2019)