Sex biased expression characterizes ~1,000 genes in mammalian liver, and impart sex differences in metabolism and disease susceptibility. The sex-dependent temporal patterns of pituitary growth hormone (GH) secretion, pulsatile in males and more continuous in females, are known to sex-differentially activate transcriptional regulators (TFs), leading to widespread sex-differences in the mouse liver transcriptome. This thesis elucidates sex-biased gene expression patterns in the following studies. Gene structures, expression patterns and species conservation are characterized for ~15,000 liver-expressed intergenic long noncoding RNAs (lncRNAs), many of which are novel. Analysis of intergenic lncRNA promoters revealed unexpected high conservation and significant enrichment of TF binding compared to protein-coding promoters. A subset of intergenic lncRNAs showed strong sex-specific and GH-dependent gene expression, and whose transcription was tightly correlated with the surrounding chromatin environment and TF binding patterns. The pervasive role of genetic factors to regulate sex-biased genes was revealed by analyzing livers with matched genotype and gene expression data from Diversity Outbred (DO) mice, an outbred population with high natural allelic variance derived from eight inbred strains. Significant associations between genetic variants and gene expression (eQTLs) were identified, including many eQTLs with a strong sex-biased association. Remarkably, a large fraction of these sex-biased eQTLs were linked to either gain or loss of sex-specific gene expression in the DO founder strain predicted to be regulated by the eQTL. Thus, genetic factors are a major contributor to the variability of sex-biased genes, which has important consequences related to the individual variability of liver phenotypes with known sex-differences. Natural genetic perturbations in DO mice were leveraged to identify candidate lncRNAs that may regulate hypophysectomy (hypox) responsiveness. Co-regulated protein-coding gene clusters were discovered based on gene expression correlations across DO mouse livers, many of which are enriched for distinct hypox response classes. LncRNAs whose expression showed unexpected significant negative correlation with protein-coding gene clusters enriched for genes of the opposite-sex bias and inverse hypox class were hypothesized to play negative regulatory role. In sum, these studies expand the characterization of the sex-biased hepatic transcriptome and reveal contributions of genetic factors to the regulation of sex bias in mammalian liver. / 2020-11-27T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/33194 |
| Date | 27 November 2018 |
| Creators | Melia, Tisha |
| Contributors | Waxman, David J |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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