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.

X chromosome agents of sexual differentiation

Abstract

Understanding sex differences in physiology and disease requires the identification of the molecular agents that cause phenotypic sex differences. Two groups of such agents are genes located on the sex chromosomes, and gonadal hormones. The former have coherent linkage to chromosomes that form differently in the two sexes under the influence of genomic forces that are not related to reproductive function, whereas the latter have a direct or indirect relationship to reproduction. Evidence published in the past 5 years supports the identification of several agents of sexual differentiation encoded by the X chromosome in mice, including Kdm5c, Kdm6a, Ogt and Xist. These X chromosome agents have wide pleiotropic effects, potentially influencing sex differences in many different tissues, a characteristic shared with the gonadal hormones. The identification of X chromosome agents of sexual differentiation will facilitate understanding of complex intersecting gene pathways underlying sex differences in disease.

Key points

  • Phenotypic sex differences arise because of the different expression levels of genes on the sex chromosomes, including unequal downstream effects of gonadal hormones.

  • Evidence in the past 5 years implicates specific X chromosome genes as agents causing sex differences in a wide variety of tissues, which is relevant to many diseases.

  • Two major groups of agents of sexual differentiation, sex chromosome genes and gonadal hormones, might differ in their relevance to reproduction because of their different evolutionary history and chromosomal linkage.

  • Sex-biasing effects of sex chromosome genes and gonadal hormones might be favoured because they produce a de novo adaptive effect or offset another disadvantageous sex difference.

  • Because gonadal hormonal and sex chromosomal agents of sexual differentiation both have pleiotropic effects, they probably produce diverse sex differences that are not all equally advantageous.

  • Sex differences in disease might occur even in tissues that function equally in healthy individuals, if the sex difference is based on different compensatory mechanisms in the two sexes.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Classes of X chromosome genes that contribute more or less to sexual differentiation.
Fig. 2: Examples of diverse sex differences caused in part by Kdm6a dose in mice.
Fig. 3: Side effects of pleiotropic agents of sexual differentiation.

References

  1. Clayton, J. A. & Collins, F. S. Policy: NIH to balance sex in cell and animal studies. Nature 509, 282–283 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  2. De Vries, G. J. Minireview: Sex differences in adult and developing brains: compensation, compensation, compensation. Endocrinology 145, 1063–1068 (2004).

    PubMed  Article  CAS  Google Scholar 

  3. Arnold, A. P. The end of gonad-centric sex determination in mammals. Trends Genet. 28, 55–61 (2012).

    CAS  PubMed  Article  Google Scholar 

  4. Arnold, A. P. Sexual differentiation of brain and other tissues: five questions for the next 50 years. Horm. Behav. 120, 104691 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Jost, A. Hormonal factors in the sex differentiation of the mammalian foetus. Philos. Trans. Roy. Soc. Lond. B Biol. Sci. 259, 119–130 (1970).

    CAS  Article  Google Scholar 

  6. Phoenix, C. H., Goy, R. W., Gerall, A. A. & Young, W. C. Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig. Endocrinology 65, 369–382 (1959).

    CAS  PubMed  Article  Google Scholar 

  7. Arnold, A. P. The organizational-activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues. Horm. Behav. 55, 570–578 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. Lowe, R., Gemma, C., Rakyan, V. K. & Holland, M. L. Sexually dimorphic gene expression emerges with embryonic genome activation and is dynamic throughout development. BMC Genomics 16, 295 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  9. Werner, R. J. et al. Sex chromosomes drive gene expression and regulatory dimorphisms in mouse embryonic stem cells. Biol. Sex. Differ. 8, 28 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  10. Bellott, D. W. et al. Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators. Nature 508, 494–499 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. Cooke, B., Hegstrom, C. D., Villeneuve, L. S. & Breedlove, S. M. Sexual differentiation of the vertebrate brain: principles and mechanisms. Front. Neuroendocrinol. 19, 323–362 (1998).

    CAS  PubMed  Article  Google Scholar 

  12. Arnold, A. P. Rethinking sex determination of non-gonadal tissues. Curr. Top. Dev. Biol. 134, 289–315 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Fang, H., Deng, X. & Disteche, C. M. X-factors in human disease: impact of gene content and dosage regulation. Hum. Mol. Genet. 30, R285–R295 (2021).

    CAS  PubMed  Article  Google Scholar 

  14. Naqvi, S. et al. Conservation, acquisition, and functional impact of sex-biased gene expression in mammals. Science 365, eaaw7317 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Capel, B. Vertebrate sex determination: evolutionary plasticity of a fundamental switch. Nat. Rev. Genet. 18, 675–689 (2017).

    CAS  PubMed  Article  Google Scholar 

  16. Disteche, C. M. Dosage compensation of the sex chromosomes and autosomes. Semin. Cell Dev. Biol. 56, 9–18 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. Hughes, J. F. & Page, D. C. The biology and evolution of mammalian Y chromosomes. Annu. Rev. Genet. 49, 507–527 (2015).

    CAS  PubMed  Article  Google Scholar 

  18. Chaligne, R. & Heard, E. X-chromosome inactivation in development and cancer. Febs. Lett. 588, 2514–2522 (2014).

    CAS  PubMed  Article  Google Scholar 

  19. Yildirim, E. et al. Xist RNA is a potent suppressor of hematologic cancer in mice. Cell 152, 727–742 (2013).

    CAS  PubMed  Article  Google Scholar 

  20. Graves, J. A. M. Sex chromosome specialization and degeneration in mammals. Cell 124, 901–914 (2006).

    PubMed  Article  CAS  Google Scholar 

  21. Dunford, A. et al. Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias. Nat. Genet. 49, 10–16 (2017).

    CAS  PubMed  Article  Google Scholar 

  22. Rubin, J. B. et al. Sex differences in cancer mechanisms. Biol. Sex. Differ. 11, 17 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Arnold, A. P. Four core genotypes and XY* mouse models: update on impact on SABV research. Neurosci. Biobehav. Rev. 119, 1–8 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Burgoyne, P. S. & Arnold, A. P. A primer on the use of mouse models for identifying direct sex chromosome effects that cause sex differences in non-gonadal tissues. Biol. Sex. Differ. 7, 68 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. Cunningham, C. M. et al. Y-chromosome gene, Uty, protects against pulmonary hypertension by reducing lung pro-inflammatory cytokines. FASEB J. https://doi.org/10.1096/fasebj.2020.34.s1.02378 (2020).

    Article  PubMed  Google Scholar 

  26. Link, J. C. et al. X chromosome dosage of histone demethylase KDM5C determines sex differences in adiposity. J. Clin. Invest. 130, 5688–5702 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Migeon, B. R. Females are Mosaics: X Inactivation and Sex Differences in Disease (Oxford Univ. Press, 2007).

  28. Charlesworth, B. & Charlesworth, D. The degeneration of Y chromosomes. Philos. Trans. R. Soc. Lond. B Biol. Sci. 355, 1563–1572 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Bachtrog, D. Y-chromosome evolution: emerging insights into processes of Y-chromosome degeneration. Nat. Rev. Genet. 14, 113–124 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. Charlesworth, D., Charlesworth, B. & Marais, G. Steps in the evolution of heteromorphic sex chromosomes. Heredity 95, 118–128 (2005).

    CAS  PubMed  Article  Google Scholar 

  31. Cotton, A. M. et al. Analysis of expressed SNPs identifies variable extents of expression from the human inactive X chromosome. Genome Biol. 14, R122 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  32. Berletch, J. B. et al. Escape from X inactivation varies in mouse tissues. PLoS Genet. 11, e1005079 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  33. Cortez, D. et al. Origins and functional evolution of Y chromosomes across mammals. Nature 508, 488–493 (2014).

    CAS  PubMed  Article  Google Scholar 

  34. Naqvi, S., Bellott, D. W., Lin, K. S. & Page, D. C. Conserved microRNA targeting reveals preexisting gene dosage sensitivities that shaped amniote sex chromosome evolution. Genome Res. 28, 474–483 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Raznahan, A. et al. Sex-chromosome dosage effects on gene expression in humans. Proc. Natl Acad. Sci. USA 115, 7398–7403 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. Carrel, L. & Willard, H. F. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434, 400–404 (2005).

    CAS  PubMed  Article  Google Scholar 

  37. Tukiainen, T. et al. Landscape of X chromosome inactivation across human tissues. Nature 550, 244–248 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  38. Delbridge, A. R. D. et al. Loss of p53 causes stochastic aberrant X-chromosome inactivation and female-specific neural tube defects. Cell Rep. 27, 442–454 (2019).

    CAS  PubMed  Article  Google Scholar 

  39. Yu, B. et al. B cell-specific XIST complex enforces X-inactivation and restrains atypical B cells. Cell 184, 1790–1803 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Pessia, E., Makino, T., Bailly-Bechet, M., McLysaght, A. & Marais, G. A. Mammalian X chromosome inactivation evolved as a dosage-compensation mechanism for dosage-sensitive genes on the X chromosome. Proc. Natl Acad. Sci. USA 109, 5346–5351 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Peeters, S. B., Cotton, A. M. & Brown, C. J. Variable escape from X-chromosome inactivation: identifying factors that tip the scales towards expression. Bioessays 36, 746–756 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Syrett, C. M. & Anguera, M. C. When the balance is broken: X-linked gene dosage from two X chromosomes and female-biased autoimmunity. J. Leukoc. Biol. 106, 919–932 (2019).

    CAS  PubMed  Article  Google Scholar 

  43. Garieri, M. et al. Extensive cellular heterogeneity of X inactivation revealed by single-cell allele-specific expression in human fibroblasts. Proc. Natl Acad. Sci. USA 115, 13015–13020 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Golden, L. C. et al. Parent-of-origin differences in DNA methylation of X chromosome genes in T lymphocytes. Proc. Natl Acad. Sci. USA 116, 26779–26787 (2019).

    CAS  PubMed Central  Article  Google Scholar 

  45. Wijchers, P. J. & Festenstein, R. J. Epigenetic regulation of autosomal gene expression by sex chromosomes. Trends Genet. 27, 132–140 (2011).

    CAS  PubMed  Article  Google Scholar 

  46. Tricarico, R., Nicolas, E., Hall, M. J. & Golemis, E. A. X- and Y-linked chromatin-modifying genes as regulators of sex-specific cancer incidence and prognosis. Clin. Cancer Res. 26, 5567–5578 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. Shpargel, K. B., Sengoku, T., Yokoyama, S. & Magnuson, T. UTX and UTY demonstrate histone demethylase-independent function in mouse embryonic development. PLoS Genet. 8, e1002964 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Godfrey, A. K. et al. Quantitative analysis of Y-chromosome gene expression across 36 human tissues. Genome Res. 30, 860–873 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Oliva, M. et al. The impact of sex on gene expression across human tissues. Science 369, eaba3066 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. Kelkar, A., Thakur, V., Ramaswamy, R. & Deobagkar, D. Characterisation of inactivation domains and evolutionary strata in human X chromosome through Markov segmentation. PLoS ONE 4, e7885 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  51. Iwase, S. et al. The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell 128, 1077–1088 (2007).

    CAS  PubMed  Article  Google Scholar 

  52. Chen, X. et al. The number of X chromosomes causes sex differences in adiposity in mice. PLoS Genet. 8, e1002709 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. Link, J. C. et al. Increased high-density lipoprotein cholesterol levels in mice with XX versus XY sex chromosomes. Arterioscler. Thromb. Vasc. Biol. 35, 1778–1786 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Kosugi, M. et al. Mutations of histone demethylase genes encoded by X and Y chromosomes, Kdm5c and Kdm5d, lead to noncompaction cardiomyopathy in mice. Biochem. Biophys. Res. Commun. 525, 100–106 (2020).

    CAS  Article  Google Scholar 

  55. Venkataramanan, S., Gadek, M., Calviello, L., Wilkins, K. & Floor, S. N. DDX3X and DDX3Y are redundant in protein synthesis. RNA 27, 1577–1588 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. Tran, N., Broun, A. & Ge, K. Lysine demethylase KDM6A in differentiation, development, and cancer. Mol. Cell Biol. 40, e00341-20 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  57. Kaneko, S. & Li, X. X chromosome protects against bladder cancer in females via a KDM6A-dependent epigenetic mechanism. Sci. Adv. 4, eaar5598 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  58. Davis, E. J. et al. The second X chromosome confers resilience against Alzheimer’s disease-related deficits in male and female mice. Sci. Transl. Med. 12, eaaz5677 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Fish, E. N. The X-files in immunity: sex-based differences predispose immune responses. Nat. Rev. Immunol. 8, 737–744 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Voskuhl, R. R. & Gold, S. M. Sex-related factors in multiple sclerosis susceptibility and progression. Nat. Rev. Neurol. 8, 255–263 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. Itoh, Y. et al. The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity. J. Clin. Invest. 130, 3852–3863 (2019).

    Article  Google Scholar 

  62. Smith-Bouvier, D. L. et al. A role for sex chromosome complement in the female bias in autoimmune disease. J. Exp. Med. 205, 1099–1108 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Doss, P. et al. Male sex chromosomal complement exacerbates the pathogenicity of Th17 cells in a chronic model of central nervous system autoimmunity. Cell Rep. 34, 108833 (2021).

    CAS  PubMed  Article  Google Scholar 

  64. Nugent, B. M., O’Donnell, C. M., Epperson, C. N. & Bale, T. L. Placental H3K27me3 establishes female resilience to prenatal insults. Nat. Commun. 9, 2555 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  65. Howerton, C. L. & Bale, T. L. Targeted placental deletion of OGT recapitulates the prenatal stress phenotype including hypothalamic mitochondrial dysfunction. Proc. Natl Acad. Sci. USA 111, 9639–9644 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. Marahrens, Y., Panning, B., Dausman, J., Strauss, W. & Jaenisch, R. Xist-deficient mice are defective in dosage compensation but not spermatogenesis. Genes Dev. 11, 156–166 (1997).

    CAS  PubMed  Article  Google Scholar 

  67. Yang, L., Kirby, J. E., Sunwoo, H. & Lee, J. T. Female mice lacking Xist RNA show partial dosage compensation and survive to term. Genes Dev. 30, 1747–1760 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Yang, L., Yildirim, E., Kirby, J. E., Press, W. & Lee, J. T. Widespread organ tolerance to Xist loss and X reactivation except under chronic stress in the gut. Proc. Natl Acad. Sci. USA 117, 4262–4272 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. Adrianse, R. L. et al. Perturbed maintenance of transcriptional repression on the inactive X-chromosome in the mouse brain after Xist deletion. Epigenetics Chromatin 11, 50 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  70. Wang, W. et al. Biological function of long non-coding RNA (lncRNA) Xist. Front. Cell Dev. Biol. 9, 645647 (2021).

    PubMed  PubMed Central  Article  Google Scholar 

  71. Wang, C. et al. Silencing of lncRNA XIST impairs angiogenesis and exacerbates cerebral vascular injury after ischemic stroke. Mol. Ther. Nucleic Acids 26, 148–160 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. Chen, X. et al. Sex difference in neural tube defects in p53-null mice is caused by differences in the complement of X not Y genes. Dev. Neurobiol. 68, 265–273 (2008).

    CAS  PubMed  Article  Google Scholar 

  73. Dean, R. & Mank, J. E. The role of sex chromosomes in sexual dimorphism: discordance between molecular and phenotypic data. J. Evol. Biol. 27, 1443–1453 (2014).

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

The author thanks his many generous collaborators, who have inspired him and educated him concerning concepts discussed here. The author is supported by NIH grants OD030496, OD026560, HD100298, HD076125, DK083561 and HL131182.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Arthur P. Arnold.

Ethics declarations

Competing interests

The author declares no competing interests.

Peer review

Peer review information

Nature Reviews Endocrinology thanks Christine Disteche, Adriana Maggi and Margaret McCarthy for their contribution to the peer review of this work.

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

Arnold, A.P. X chromosome agents of sexual differentiation. Nat Rev Endocrinol 18, 574–583 (2022). https://doi.org/10.1038/s41574-022-00697-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-022-00697-0

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing