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

Abstract

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 sex-differentially 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.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.06312-11.

ACKNOWLEDGMENTS

This work was supported by Public Health Service grant DK-33765 from the National Institutes of Health (to D.J.W.).

We thank Aarathi Sugathan of our laboratory and Ernest Fraenkel (Department of Biological Engineering, MIT) and Stuart Levine (Biomicro Center, MIT) for useful discussions.

There are no competing interests to be declared.

D.J.W. conceived and designed the experiments; E.V.L. performed the laboratory-based studies; Y.Z. analyzed the ChIP-Seq data and prepared figures and tables for publication; Y.Z. and D.J.W. wrote the manuscript.