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.
Highlights
The nuclear receptor (NR) Retinoic X Receptor (RXRa; NR2B1) is the obligate heterodimerization partner for .14 Class II Nuclear Receptors (NRs) including: LXRa,b (NR1H2,3), PPARa b,c (NR1C1–3), RARa b,c (NR1B1–3), FXR (NR1H4), PXR (NR1I2), TR (NR1A1) and VDR (NR1I1) [1]
There were nearly an equal number of genes in both genders (12,771 male and 12,693 female) associated with Retinoid X Receptor alpha (RXRa) binding sites, with the vast majority (11,660/,92%) in common (Fig. 1C). This indicates an average of,3–4 RXRa binding sites in each of the .12,500 expressed and potentially RXRa-regulated genes in mouse liver. This large number of common and gender-specific RXRa binding sites in male and female livers (.45,0000) spread across,12,000 genes makes RXRa, to our knowledge, one of the most broadly distributed transcription factor in mouse liver chromatin found to date
No significant differences in RXRa binding site geographic distribution profiles or in chromosomal distribution for RXRa and Pol2 binding sites were noted between genders (Fig. S1A and S1B)
Summary
The nuclear receptor (NR) Retinoic X Receptor (RXRa; NR2B1) is the obligate heterodimerization partner for .14 Class II NRs including: LXRa,b (NR1H2,3), PPARa b,c (NR1C1–3), RARa b,c (NR1B1–3), FXR (NR1H4), PXR (NR1I2), TR (NR1A1) and VDR (NR1I1) [1]. The nuclear receptor (NR) Retinoic X Receptor (RXRa; NR2B1) is the obligate heterodimerization partner for .14. Class II NRs including: LXRa,b (NR1H2,3), PPARa b,c (NR1C1–3), RARa b,c (NR1B1–3), FXR (NR1H4), PXR (NR1I2), TR (NR1A1) and VDR (NR1I1) [1]. The functionality of RXRa:partner heterodimerization complexes can be categorized as permissive (such as FXR, LXRa and PPARa b,c) or non-permissive (such as RARa and VDR), depending upon their responses to ligands for each partner [1]. Activation of permissive heterodimers occurs by ligands for both RXRa and its partner, either independently or together, the latter results in synergistic activation of gene transcription, whereas activation of non-permissive RXRa heterodimers occurs through ligand binding of the NR-partner and is unaffected by the presence of an RXRa agonist
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