The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity.

Multiple sclerosis (MS) is a putative T cell-mediated autoimmune disease. As with many autoimmune diseases, females are more susceptible than males. Sexual dimorphisms may be due to differences in sex hormones, sex chromosomes, or both. Regarding sex chromosome genes, a small percentage of X chromosome genes escape X inactivation and have higher expression in females (XX) compared with males (XY). Here, high-throughput gene expression analysis in CD4+ T cells showed that the top sexually dimorphic gene was Kdm6a, a histone demethylase on the X chromosome. There was higher expression of Kdm6a in females compared with males in humans and mice, and the four core genotypes (FCG) mouse model showed higher expression in XX compared with XY. Deletion of Kdm6a in CD4+ T cells ameliorated clinical disease and reduced neuropathology in the classic CD4+ T cell-mediated autoimmune disease experimental autoimmune encephalomyelitis (EAE). Global transcriptome analysis in CD4+ T cells from EAE mice with a specific deletion of Kdm6a showed upregulation of Th2 and Th1 activation pathways and downregulation of neuroinflammation signaling pathways. Together, these data demonstrate that the X escapee Kdm6a regulates multiple immune response genes, providing a mechanism for sex differences in autoimmune disease susceptibility.

[1]  R. Voskuhl,et al.  Sex is a biological variable — in the brain too , 2019, Nature.

[2]  B. Viollet,et al.  Metformin directly targets the H3K27me3 demethylase KDM6A/UTX , 2018, Aging cell.

[3]  Y. Ao,et al.  Cell-specific and region-specific transcriptomics in the multiple sclerosis model: Focus on astrocytes , 2017, Proceedings of the National Academy of Sciences.

[4]  R. Voskuhl,et al.  Oestrogen receptor β ligand acts on CD11c+ cells to mediate protection in experimental autoimmune encephalomyelitis , 2017, Brain : a journal of neurology.

[5]  J. Starmer,et al.  UTX-guided neural crest function underlies craniofacial features of Kabuki syndrome , 2017, Proceedings of the National Academy of Sciences.

[6]  Nan Li,et al.  Demethylase Kdm6a epigenetically promotes IL-6 and IFN-β production in macrophages. , 2017, Journal of autoimmunity.

[7]  A. Arnold,et al.  A primer on the use of mouse models for identifying direct sex chromosome effects that cause sex differences in non-gonadal tissues , 2016, Biology of Sex Differences.

[8]  C. Palii,et al.  UTX demethylase activity is required for satellite cell-mediated muscle regeneration. , 2016, The Journal of clinical investigation.

[9]  Li Guo,et al.  Metformin ameliorates the development of experimental autoimmune encephalomyelitis by regulating T helper 17 and regulatory T cells in mice , 2016, Journal of Neuroimmunology.

[10]  M. Cam,et al.  Histone H3 Lysine 27 demethylases Jmjd3 and Utx are required for T-cell differentiation , 2015, Nature Communications.

[11]  W. Cao,et al.  The histone H3 lysine-27 demethylase Jmjd3 plays a critical role in specific regulation of Th17 cell differentiation. , 2015, Journal of molecular cell biology.

[12]  A. Arnold,et al.  Four Core Genotypes mouse model: localization of the Sry transgene and bioassay for testicular hormone levels , 2015, BMC Research Notes.

[13]  William Stafford Noble,et al.  Escape from X Inactivation Varies in Mouse Tissues , 2015, PLoS genetics.

[14]  Michael B. Stadler,et al.  QuasR: quantification and annotation of short reads in R , 2014, Bioinform..

[15]  K. Zhao,et al.  Critical role of histone demethylase Jmjd3 in the regulation of CD4+ T cell differentiation , 2014, Nature Communications.

[16]  J. Starmer,et al.  KDM6 Demethylase Independent Loss of Histone H3 Lysine 27 Trimethylation during Early Embryonic Development , 2014, PLoS genetics.

[17]  U. Oppermann,et al.  Human UTY(KDM6C) Is a Male-specific Nϵ-Methyl Lysyl Demethylase , 2014, The Journal of Biological Chemistry.

[18]  Björn Usadel,et al.  Trimmomatic: a flexible trimmer for Illumina sequence data , 2014, Bioinform..

[19]  A. Arnold,et al.  XY sex chromosome complement, compared with XX, in the CNS confers greater neurodegeneration during experimental autoimmune encephalomyelitis , 2014, Proceedings of the National Academy of Sciences.

[20]  Min Gyu Lee,et al.  Trans-tail regulation of MLL4-catalyzed H3K4 methylation by H4R3 symmetric dimethylation is mediated by a tandem PHD of MLL4. , 2012, Genes & development.

[21]  Steve D. M. Brown,et al.  The mammalian gene function resource: the international knockout mouse consortium , 2012, Mammalian Genome.

[22]  S. Gold,et al.  The XX sex chromosome complement in mice is associated with increased spontaneous lupus compared with XY , 2012, Annals of the rheumatic diseases.

[23]  M. Gershwin,et al.  The X chromosome and immune associated genes. , 2012, Journal of autoimmunity.

[24]  S. Gold,et al.  Sex-related factors in multiple sclerosis susceptibility and progression , 2012, Nature Reviews Neurology.

[25]  Simon C. Potter,et al.  Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis , 2011, Nature.

[26]  J. Harrow,et al.  A conditional knockout resource for the genome-wide study of mouse gene function , 2011, Nature.

[27]  M. Nagarkatti,et al.  CD44 Reciprocally Regulates the Differentiation of Encephalitogenic Th1/Th17 and Th2/Regulatory T Cells through Epigenetic Modulation Involving DNA Methylation of Cytokine Gene Promoters, Thereby Controlling the Development of Experimental Autoimmune Encephalomyelitis , 2011, The Journal of Immunology.

[28]  C. Disteche,et al.  Genes that escape from X inactivation , 2011, Human Genetics.

[29]  Y. Ao,et al.  Neuroprotection mediated through estrogen receptor-α in astrocytes , 2011, Proceedings of the National Academy of Sciences.

[30]  C. Libert,et al.  The X chromosome in immune functions: when a chromosome makes the difference , 2010, Nature Reviews Immunology.

[31]  Fan Yang,et al.  Escape from X inactivation in mice and humans , 2010, Genome Biology.

[32]  J. Shendure,et al.  Global survey of escape from X inactivation by RNA-sequencing in mouse. , 2010, Genome research.

[33]  C. Palii,et al.  UTX mediates demethylation of H3K27me3 at muscle-specific genes during myogenesis , 2010, The EMBO journal.

[34]  Davis J. McCarthy,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[35]  O. Ohara,et al.  Mina, an Il4 repressor, controls T helper type 2 bias , 2009, Nature Immunology.

[36]  M. Nagarkatti,et al.  Role of CD44 in the Differentiation of Th1 and Th2 Cells: CD44-Deficiency Enhances the Development of Th2 Effectors in Response to Sheep RBC and Chicken Ovalbumin1 , 2009, The Journal of Immunology.

[37]  Shailendra Giri,et al.  Metformin Attenuated the Autoimmune Disease of the Central Nervous System in Animal Models of Multiple Sclerosis1 , 2009, The Journal of Immunology.

[38]  A. Bradley,et al.  Agouti C57BL/6N embryonic stem cells for mouse genetic resources , 2009, Nature Methods.

[39]  A. Arnold,et al.  What does the “four core genotypes” mouse model tell us about sex differences in the brain and other tissues? , 2009, Frontiers in Neuroendocrinology.

[40]  M. Nagarkatti,et al.  CD44 mobilization in allogeneic dendritic cell–T cell immunological synapse plays a key role in T cell activation , 2008, Journal of leukocyte biology.

[41]  A. Arnold,et al.  A role for sex chromosome complement in the female bias in autoimmune disease , 2008, The Journal of experimental medicine.

[42]  C. Disteche,et al.  Sex-Specific Differences in Expression of Histone Demethylases Utx and Uty in Mouse Brain and Neurons , 2008, The Journal of Neuroscience.

[43]  T. Veenstra,et al.  Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases , 2007, Proceedings of the National Academy of Sciences.

[44]  Howard Y. Chang,et al.  A histone H3 lysine 27 demethylase regulates animal posterior development , 2007, Nature.

[45]  S. Gabriel,et al.  Risk alleles for multiple sclerosis identified by a genomewide study. , 2007, The New England journal of medicine.

[46]  C. Croce,et al.  Knockdown of ALR (MLL2) Reveals ALR Target Genes and Leads to Alterations in Cell Adhesion and Growth , 2006, Molecular and Cellular Biology.

[47]  J. Zachary,et al.  Evidence that the Y chromosome influences autoimmune disease in male and female mice. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[48]  A. Arnold,et al.  Sexually dimorphic expression of Usp9x is related to sex chromosome complement in adult mouse brain , 2005, The European journal of neuroscience.

[49]  G. J. Vries,et al.  Minireview: Sex differences in adult and developing brains: compensation, compensation, compensation. , 2004 .

[50]  D. Lubahn,et al.  Estrogen Receptor α Mediates Estrogen’s Immune Protection in Autoimmune Disease , 2003, The Journal of Immunology.

[51]  C. Disteche,et al.  Escape from X inactivation , 2003, Cytogenetic and Genome Research.

[52]  A. Arnold,et al.  Sex differences in sex chromosome gene expression in mouse brain. , 2002, Human molecular genetics.

[53]  Caroline C. Whitacre,et al.  A Gender Gap in Autoimmunity , 1999, Science.

[54]  A. Monaco,et al.  The UTX gene escapes X inactivation in mice and humans. , 1998, Human molecular genetics.

[55]  S. Rastan,et al.  Requirement for Xist in X chromosome inactivation , 1996, Nature.

[56]  C. Tashima.  Estrogen receptor assay. , 1977, JAMA.

[57]  HlROSHI Shibasaki,et al.  Sex difference of multiple sclerosis in Japan , 1976, Neurology.

[58]  E. Gunde,et al.  Sex-Based Differences in Multiple Sclerosis (MS): Part II: Rising Incidence of Multiple Sclerosis in Women and the Vulnerability of Men to Progression of this Disease. , 2015, Current topics in behavioral neurosciences.

[59]  D. Lubahn,et al.  Estrogen receptor alpha mediates estrogen's immune protection in autoimmune disease. , 2003, Journal of immunology.