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Role of growth hormone and chromatin structure in regulation of sex differences in mouse liver gene expression

Sex differences in mammalian gene expression result from differences in genotypic sex as well as in hormonal regulators between males and females. In rat, mouse and human liver, ~1000 genes are expressed in a sex-dependent manner, and contribute to sex differences in metabolism of drugs, steroids and lipids, and in liver and cardiovascular disease risk. In rats and mice, sex-biased liver gene expression is primarily dictated by the sexually dimorphic pattern of pituitary growth hormone (GH) release and its STAT5-dependent transcriptional activities. Studies presented in this thesis include the following. (1) A computational approach based on DNA sequence and phylogenetic conservation was developed and used to identify novel functional STAT5 binding sites - both consensus and non-consensus STAT5 sequences - near prototypic GH-responsive genes. (2) Global gene expression analysis of livers from pituitary-ablated male and female mice identified four major classes of sex-biased genes differing in their profiles of GH dependence. (3) Sex-differences in DNase-hypersensitive sites (DHS, corresponding to open chromatin regions) were identified genome-wide in mouse liver. These sex-differential DHSs were enriched for association with sex-biased genes, but a majority was distant from sex-biased genes. Furthermore, many were responsive to GH treatment, demonstrating that GH-mediated regulation involves chromatin remodeling. Analysis of sequence motifs enriched at sex-biased DHSs implicated STAT5 and novel transcription factors such as PBX1 and TAL1 in sex-biased gene regulation. (4) Genome-wide mapping of histone modifications revealed distinct mechanisms of sex-biased gene regulation in male and female liver: sex-dependent K27me3-mediated repression is an important mechanism of repression of female-biased, but not of male-biased, genes, and a sex-dependent K4me1 distribution, suggesting nucleosome repositioning by pioneer factors, is observed at male-biased, but not female-biased, regulatory sites. STAT5-mediated activation was most strongly associated with sex-biased chromatin modifications, while BCL6-mediated repression primarily occurs in association with sex-independent chromatin modifications, both at binding sites and at target genes. The relationships between sex-dependent chromatin accessibility, chromatin modifications and transcription-factor binding uncovered by these studies help elucidate the molecular mechanisms governing sex-differential gene expression, and underscore the utility of functional genomic and epigenetic studies as tools for elucidating transcriptional regulation in complex mammalian systems.

Identiferoai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/13139
Date23 September 2015
CreatorsSugathan, Aarathi
Source SetsBoston University
Languageen_US
Detected LanguageEnglish
TypeThesis/Dissertation

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