Role of Histone-3 Lysine 27 Trimethylation (K27-me3) in Repression of Female-Specific, Growth Hormone-Regulated Genes in Male Mouse Liver

Sugathan, Aarathi; Laz, Ekaterina V; Rampersaud, Andy; Waxman, David J.

doi:10.1210/endo-meetings.2011.part2.p35.p2-330

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“…When comparing STAT5 and BCL6 peak sets, the overlap between the peak sets being compared was calculated after trimming the peaks to a total width of 600 nt centered at the peak summit. ChIP-Seq peaks were compared to chromatin mark data sets (57) and to the set of 72,862 global mouse liver DNase hypersensitivity (DHS) sites identified previously (39), which correspond to open chromatin regions. For both the male and female DHS and H3-K27me3 data sets, sequence reads in the liver samples comprising each set were rescaled based on the total number of mapped sequence reads, to facilitate comparisons between male and female liver samples.…”

Section: Methodsmentioning

confidence: 99%

Dynamic, Sex-Differential STAT5 and BCL6 Binding to Sex-Biased, Growth Hormone-Regulated Genes in Adult Mouse Liver

Zhang

Laz

Waxman

2012

Molecular and Cellular Biology

149

261

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Sex-dependent pituitary growth hormone (GH) secretory patterns determine the sex-biased expression of >1,000 genes in mouse and rat liver, affecting lipid and drug metabolism, inflammation, and disease. A fundamental biological question is how robust differential expression can be achieved for hundreds of sex-biased genes simply based on the GH input signal pattern: pulsatile GH stimulation in males versus near-continuous GH exposure in females. STAT5 is an essential transcriptional mediator of the sex-dependent effects of GH in the liver, but the mechanisms that underlie its sex-dependent actions are obscure. Here we elucidate the dynamic, sex-dependent binding of STAT5 and the GH/STAT5-regulated repressor BCL6 to mouse liver chromatin genome wide, revealing a counteractive interplay between these two regulators of sex differences in liver gene expression. Our findings establish a close correlation between sex-dependent STAT5 binding and sex-biased target gene expression. Moreover, sex-dependent STAT5 binding correlated positively with sex-biased DNase hypersensitivity and H3-K4me1 and H3-K4me3 (activating) marks, correlated negatively with sex-biased H3-K27me3 (repressive) marks, and was associated with sexdifferentially enriched motifs for HNF6/CDP factors. Importantly, BCL6 binding was preferentially associated with repression of female-biased STAT5 targets in male liver. Furthermore, BCL6 and STAT5 common targets but not BCL6 unique targets showed strong enrichment for lipid and drug metabolism. These findings provide a comprehensive, genome-wide view of the mechanisms whereby these two GH-regulated transcription factors establish and maintain sex differences affecting liver physiology and disease. The approaches used here to characterize sex-dependent STAT5 and BCL6 binding can be applied to other condition-specific regulatory factors and binding sites and their interplay with cooperative chromatin binding factors.

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Section: Methodsmentioning

confidence: 99%