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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.

SUBMITTER: Sugathan A

PROVIDER: S-EPMC3753870 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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

Sugathan Aarathi A Waxman David J DJ

Molecular and cellular biology 20130708 18

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 ...[more]

PMID: 23836885

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Project description:In male mice, sepsis-induced cardiomyopathy develops as a result of dysregulation of myocardial calcium (Ca) handling, leading to depressed cellular Ca transients (?Cai). ?Cai depression is partially due to inhibition of sarcoplasmic reticulum Ca ATP-ase (SERCA) via oxidative modifications, which are partially opposed by cGMP generated by the enzyme soluble guanylyl cyclase (sGC). Whether similar mechanisms underlie sepsis-induced cardiomyopathy in female mice is unknown.Male and female C57Bl/6J mice (WT), and mice deficient in the sGC ?1 subunit activity (sGC?1), were challenged with lipopolysaccharide (LPS, ip). LPS induced mouse death and cardiomyopathy (manifested as the depression of left ventricular ejection fraction by echocardiography) to a similar degree in WT male, WT female, and sGC?1 male mice, but significantly less in sGC?1 female mice. We measured sarcomere shortening and ?Cai in isolated, externally paced cardiomyocytes, at 37°C. LPS depressed sarcomere shortening in both WT male and female mice. Consistent with previous findings, in male mice, LPS induced a decrease in ?Cai (to 30?±?2% of baseline) and SERCA inhibition (manifested as the prolongation of the time constant of Ca decay, ?Ca, to 150?±?5% of baseline). In contrast, in female mice, the depression of sarcomere shortening induced by LPS occurred in the absence of any change in ?Cai, or SERCA activity. This suggested that, in female mice, the causative mechanism lies downstream of the Ca transients, such as a decrease in myofilament sensitivity for Ca. The depression of sarcomere shortening shortening after LPS was less severe in female sGC?1 mice than in WT female mice, indicating that cGMP partially mediates cardiomyocyte dysfunction.These results suggest, therefore, that LPS-induced cardiomyopathy develops through distinct sex-specific myocardial mechanisms. While in males LPS induces sGC-independent decrease in ?Cai, in female mice LPS acts downstream of ?Cai, possibly via sGC-dependent myofilament dysfunction.

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

Publications

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

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