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


Autoři: Dana Lau-Corona aff001;  Woo Kyun Bae aff002;  Lothar Hennighausen aff002;  David J. Waxman aff001
Působiště autorů: Department of Biology and Bioinformatics Program, Boston University, Boston, Massachusetts, United States of America aff001;  Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America aff002;  Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea aff003
Vyšlo v časopise: Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2. PLoS Genet 16(5): e32767. doi:10.1371/journal.pgen.1008796
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008796

Souhrn

Sex differences in the incidence and progression of many liver diseases, including liver fibrosis and hepatocellular carcinoma, are associated with sex-biased hepatic expression of hundreds of genes. 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 and growth hormone-regulated chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive chromatin mark deposited at many strongly female-biased genes in male mouse liver, but not at male-biased genes in female liver, and is catalyzed by polycomb repressive complex-2 through its homologous catalytic subunits, Ezh1 and Ezh2. Here, we used Ezh1-knockout mice with a hepatocyte-specific knockout of Ezh2 to investigate 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 were 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. Further, Ezh1/Ezh2 deficiency in male liver, and to a lesser extent in female liver, led to up regulation of many genes linked to liver fibrosis and liver cancer, which may contribute to the observed liver pathologies and the increased sensitivity of these mice to hepatotoxin exposure. Thus, Ezh1/Ezh2-catalyzed H3K27-trimethyation regulates sex-dependent genetic programs in liver metabolism and liver fibrosis through its sex-dependent effects on the epigenome, and may thereby determine the sex-bias in liver disease susceptibility.

Klíčová slova:

Fatty liver – Gene expression – Gene regulation – Histones – Chromatin – Liver diseases – Liver fibrosis – Mouse models


Zdroje

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