title: Genome-wide analysis of chromatin states reveals distinct mechanisms of sex-dependent gene regulation in male and female mouse liver.
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.
authors.affiliation: Division of Cell and Molecular Biology, Department of Biology and Bioinformatics Program, Boston University, Boston, Massachusetts, USA.
authors.forename: Aarathi
authors.initials: A
authors.lastname: Sugathan
authors.forename: David J
authors.initials: DJ
authors.lastname: Waxman
mesh_terms: D000818:Animals; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D003850:Deoxyribonuclease I / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D005809:Genes, Regulator; D055106:Genome-Wide Association Study; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008745:Methylation; D051379:Mice; D005810:Multigene Family; D051560:Proto-Oncogene Proteins c-bcl-6; D050799:STAT5 Transcription Factor / Q000378:metabolism; D012727:Sex Characteristics; D024363:Transcription Initiation Site
chemical_list: C490010:Bcl6 protein, mouse; D002843:Chromatin; D004268:DNA-Binding Proteins; C496500:Foxa1 protein, mouse; C496503:Foxa2 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; D006657:Histones; D051560:Proto-Oncogene Proteins c-bcl-6; D050799:STAT5 Transcription Factor; D051542:Hepatocyte Nuclear Factor 3-beta; D003850:Deoxyribonuclease I