Sexually Dimorphic Genome-Wide Binding of Retinoid X Receptor alpha (RXRα) Determines Male-Female Differences in the Expression of Hepatic Lipid Processing Genes in Mice

• Type of Material: Article
• Authors: Astrid Kosters, Emory University; Deqiang Sun, Baylor College of Medicine; Hao Wu, Emory University; Feng Tian, Baylor College of Medicine; Julio C. Felix, Baylor College of Medicine; Wei Li, Baylor College of Medicine; Saul Karpen, Emory University
• Language: English
• Date: 2013
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2013 Kosters et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0071538
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 8
• Issue: 8
• Start Page: e71538
• End Page: e71538
• Grant/Funding Information: Funding was provided by NIH RC1-DK86577 to SJK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Research Categories: Health Sciences, General

Abstract

Many hepatic functions including lipid metabolism, drug metabolism, and inflammatory responses are regulated in a sex-specific 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 (RXRα) is an obligate partner for multiple NRs and considered a master regulator of hepatic gene expression, yet the full extent of RXRα chromatin binding in male and female livers is unclear. ChIP-Seq analysis of RXRα 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 RXRα-binding and RNA levels were determined by ChIP-qPCR and qPCR, respectively. ChIP-Seq revealed 47,845 (male) and 46,877 (female) RXRα binding sites (BS), associated with ~12,700 unique genes in livers of both genders, with 91% shared between sexes. RXRα-binding showed significant enrichment for 2227 and 1498 unique genes in male and female livers, respectively. Correlating RXRα 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. RXRα activation using LG268 confirmed RXRα-binding was 2–3 fold increased in female livers at multiple newly identified RXRα 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 RXRα regulation of sexually-dimorphic responses for these genes. RXRα 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.