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bioRxiv · 10.1101/577056

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2

Lau-Corona, D.·Bae, W. K.·Hennighausen, L.·Waxman, D. J.
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Abstract

BackgroundSex differences in the incidence and progression of many liver diseases, including liver fibrosis and hepatocellular carcinoma, are associated with sex-biased expression of hundreds of genes in the liver. This sexual dimorphism is largely determined by the sex-specific pattern of pituitary growth hormone secretion, which controls a transcriptional regulatory network operative in the context of sex-biased chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive chromatin mark that is specifically deposited by polycomb repressive complex-2, via its homologous catalytic subunits Ezh1 and Ezh2, at many strongly female-biased genes in male mouse liver, but not at male-biased genes in female liver.\n\nResultsWe used Ezh1-knockout mice with a hepatocyte-specific knockout of Ezh2 to elucidate the sex bias of liver H3K27-trimethylation and its functional role in regulating sex-differences in the liver. Combined hepatic Ezh1/Ezh2 deficiency led to a significant loss of sex-biased gene expression, particularly in male liver, where many female-biased genes increased in expression while male-biased genes showed decreased expression. The associated loss of H3K27me3 marks, and increases in the active enhancer marks H3K27ac and H3K4me1, were also more pronounced in male liver. Many genes linked to liver fibrosis and hepatocellular carcinoma were induced in Ezh1/Ezh2-deficient livers, which may contribute to the increased sensitivity of these mice to hepatotoxin-induced liver pathology.\n\nConclusionsEzh1/Ezh2-catalyzed H3K27-trimethyation is thus essential for the sex-dependent epigenetic regulation of liver chromatin states controlling phenotypic sex differences in liver metabolism and liver fibrosis, and may be a critical determinant of the sex-bias in liver disease susceptibility.

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Lau-Corona, D., Bae, W. K., Hennighausen, L., Waxman, D. J.. 2019-03-14. Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2. https://doi.org/10.1101/577056

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