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Plos One : Sexually Dimorphic Genome-wide Binding of Retinoid X Receptor Alpha Rxra Determines Male-female Differences in the Expression of Hepatic Lipid Processing Genes in Mice, Volume 8

By Wendong Huang

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Book Id: WPLBN0003966606
Format Type: PDF eBook :
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Reproduction Date: 2015

Title: Plos One : Sexually Dimorphic Genome-wide Binding of Retinoid X Receptor Alpha Rxra Determines Male-female Differences in the Expression of Hepatic Lipid Processing Genes in Mice, Volume 8  
Author: Wendong Huang
Volume: Volume 8
Language: English
Subject: Journals, Science, Medical Science
Collections: Periodicals: Journal and Magazine Collection (Contemporary)
Historic
Publication Date:
Publisher: Plos

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Huang, W. (n.d.). Plos One : Sexually Dimorphic Genome-wide Binding of Retinoid X Receptor Alpha Rxra Determines Male-female Differences in the Expression of Hepatic Lipid Processing Genes in Mice, Volume 8. Retrieved from http://netlibrary.net/


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Description : Many hepatic functions including lipid metabolism, drug metabolism, and inflammatory responses are regulated in a sexspecific manner due to distinct patterns of hepatic gene expression between males and females. Regulation for the majority of these genes is under control of Nuclear Receptors (NRs). Retinoid X Receptor alpha (RXRa) is an obligate partner for multiple NRs and considered a master regulator of hepatic gene expression, yet the full extent of RXRa chromatin binding in male and female livers is unclear. ChIP-Seq analysis of RXRa and RNA Polymerase2 (Pol2) binding was performed livers of both genders and combined with microarray analysis. Mice were gavage-fed with the RXR ligand LG268 for 5 days (30 mg/ kg/day) and RXRa-binding and RNA levels were determined by ChIP-qPCR and qPCR, respectively. ChIP-Seq revealed 47,845 (male) and 46,877 (female) RXRa binding sites (BS), associated with ,12,700 unique genes in livers of both genders, with 91% shared between sexes. RXRa-binding showed significant enrichment for 2227 and 1498 unique genes in male and female livers, respectively. Correlating RXRa binding strength with Pol2-binding revealed 44 genes being male-dominant and 43 female-dominant, many previously unknown to be sexually-dimorphic. Surprisingly, genes fundamental to lipid metabolism, including Scd1, Fasn, Elovl6, and Pnpla3-implicated in Fatty Liver Disease pathogenesis, were predominant in females. RXRa activation using LG268 confirmed RXRa-binding was 2–3 fold increased in female livers at multiple newly identified RXRa BS including for Pnpla3 and Elovl6, with corresponding ,10-fold and ,2-fold increases in Pnpla3 and Elovl6 RNA respectively in LG268-treated female livers, supporting a role for RXRa regulation of sexually-dimorphic responses for these genes. RXRa appears to be one of the most widely distributed transcriptional regulators in mouse liver and is engaged in determining sexually-dimorphic expression of key lipid-processing genes, suggesting novel gender- and gene-specific responses to NR-based treatments for lipid-related liver diseases

 

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