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| Status |
Public on Dec 18, 2011 |
| Title |
Dynamic, sex-differential STAT5 and BCL6 binding to sex-biased, growth hormone-regulated genes in adult mouse liver |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
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 vs. 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, revealing the counteractive interplay between these two regulators of liver sex-specificity. 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 co-operative chromatin-binding factors.
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| Overall design |
Mouse livers were excised from individual male and female mice killed at either a peak of STAT5 binding activity, or during the growth hormone (GH) interpulse interval, when STAT5 activity is either low (females) or essentially undetectable (males). Sonicated, cross-linked liver nuclear chromatin was then used to identify STAT5 binding sites by ChIP-Seq.
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| Contributor(s) |
Zhang Y, Laz EV, Waxman DJ |
| Citation(s) |
22158971 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 DK033765 |
Regulation of Sex Differences in Liver Metabolism |
BOSTON UNIVERSITY CHARLES RIVER CAMPUS |
DAVID J WAXMAN |
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| Submission date |
Aug 22, 2011 |
| Last update date |
May 15, 2019 |
| Contact name |
David J. Waxman |
| E-mail(s) |
djw@bu.edu
|
| Organization name |
Boston University
|
| Department |
Department of Biology and Bioinformatics Program
|
| Street address |
5 Cummington Mall
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| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02215 |
| Country |
USA |
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| Platforms (1) |
| GPL9250 |
Illumina Genome Analyzer II (Mus musculus) |
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| Samples (19)
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| Relations |
| SRA |
SRP007992 |
| BioProject |
PRJNA145617 |
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