Genome-wide analysis of chromatin states reveals distinct mechanisms of sex-dependent gene regulation in male and female mouse liver

Mol Cell Biol. 2013 Sep;33(18):3594-610. doi: 10.1128/MCB.00280-13. Epub 2013 Jul 8.

Abstract

Chromatin state maps were developed to elucidate sex differences in chromatin structure and their impact on sex-differential chromatin accessibility and sex-biased gene expression in mouse liver. Genes in active, inactive, and poised chromatin states exhibited differential responsiveness to ligand-activated nuclear receptors and distinct enrichments for functional gene categories. Sex-biased genes were clustered by chromatin environments and mapped to DNase-hypersensitive sites (DHS) classified by sex bias in chromatin accessibility and enhancer modifications. Results were integrated with genome-wide binding data for five transcription factors implicated in growth hormone-regulated, sex-biased liver gene expression, leading to the following findings. (i) Sex-biased DHS, but not sex-biased genes, are frequently characterized by sex-differential chromatin states, indicating distal regulation. (ii) Trimethylation of histone H3 at K27 (H3K27me3) is a major sex-biased repressive mark at highly female-biased but not at highly male-biased genes. (iii) FOXA factors are associated with sex-dependent chromatin opening at male-biased but not female-biased regulatory sites. (iv) Sex-biased STAT5 binding is enriched at sex-biased DHS marked as active enhancers and preferentially targets sex-biased genes with sex-differences in local chromatin marks. (v) The male-biased repressor BCL6 preferentially targets female-biased genes and regulatory sites in a sex-independent chromatin state. (vi) CUX2, a female-specific repressor of male-biased genes, also activates strongly female-biased genes, in association with loss of H3K27me3 marks. Chromatin states are thus a major determinant of sex-biased chromatin accessibility and gene expression, with FOXA pioneer factors proposed to confer sex-dependent chromatin opening and STAT5, but not BCL6, regulating sex-biased genes by binding to sites in a sex-biased chromatin state.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Chromatin / genetics*
  • Chromatin / metabolism*
  • DNA-Binding Proteins / metabolism
  • Deoxyribonuclease I / metabolism
  • Enhancer Elements, Genetic
  • Epigenesis, Genetic
  • Female
  • Gene Expression Regulation
  • Genes, Regulator
  • Genome-Wide Association Study
  • Hepatocyte Nuclear Factor 3-alpha / metabolism
  • Hepatocyte Nuclear Factor 3-beta / metabolism
  • Histones / chemistry
  • Histones / metabolism
  • Liver / metabolism*
  • Male
  • Methylation
  • Mice
  • Multigene Family
  • Proto-Oncogene Proteins c-bcl-6
  • STAT5 Transcription Factor / metabolism
  • Sex Characteristics*
  • Transcription Initiation Site

Substances

  • Bcl6 protein, mouse
  • Chromatin
  • DNA-Binding Proteins
  • Foxa1 protein, mouse
  • Foxa2 protein, mouse
  • Hepatocyte Nuclear Factor 3-alpha
  • Histones
  • Proto-Oncogene Proteins c-bcl-6
  • STAT5 Transcription Factor
  • Hepatocyte Nuclear Factor 3-beta
  • Deoxyribonuclease I