| First Author | Kosters A | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 8 | Pages | e71538 |
| PubMed ID | 23977068 | Mgi Jnum | J:206346 |
| Mgi Id | MGI:5550048 | Doi | 10.1371/journal.pone.0071538 |
| Citation | Kosters A, et al. (2013) Sexually dimorphic genome-wide binding of retinoid X receptor alpha (RXRalpha) determines male-female differences in the expression of hepatic lipid processing genes in mice. PLoS One 8(8):e71538 |
| abstractText | 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 (RXRalpha) is an obligate partner for multiple NRs and considered a master regulator of hepatic gene expression, yet the full extent of RXRalpha chromatin binding in male and female livers is unclear. ChIP-Seq analysis of RXRalpha 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 RXRalpha-binding and RNA levels were determined by ChIP-qPCR and qPCR, respectively. ChIP-Seq revealed 47,845 (male) and 46,877 (female) RXRalpha binding sites (BS), associated with approximately 12,700 unique genes in livers of both genders, with 91% shared between sexes. RXRalpha-binding showed significant enrichment for 2227 and 1498 unique genes in male and female livers, respectively. Correlating RXRalpha 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. RXRalpha activation using LG268 confirmed RXRalpha-binding was 2-3 fold increased in female livers at multiple newly identified RXRalpha BS including for Pnpla3 and Elovl6, with corresponding approximately 10-fold and approximately 2-fold increases in Pnpla3 and Elovl6 RNA respectively in LG268-treated female livers, supporting a role for RXRalpha regulation of sexually-dimorphic responses for these genes. RXRalpha 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. |
