title: 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.
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.
authors: Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors: Astrid
authors: A
authors: Kosters
authors: Deqiang
authors: D
authors: Sun
authors: Hao
authors: H
authors: Wu
authors: Feng
authors: F
authors: Tian
authors: Julio C
authors: JC
authors: Felix
authors: Wei
authors: W
authors: Li
authors: Saul J
authors: SJ
authors: Karpen
mesh_terms: D000818:Animals; D001665:Binding Sites; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D063990:Gene Ontology; D016678:Genome / Q000235:genetics*; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D009930:Organic Chemicals / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D012319:RNA Polymerase II / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000819:agonists / Q000378:metabolism*; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D024363:Transcription Initiation Site
chemical_list: D002843:Chromatin; C423914:LG 268; D009930:Organic Chemicals; D047490:Retinoid X Receptor alpha; D012319:RNA Polymerase II
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