Abstract
BackgroundIn a previous genome-wide analysis of FXR binding to hepatic chromatin, we noticed that an extra nuclear receptor (NR) half-site was co-enriched close to the FXR binding IR-1 elements and we provided limited support that the monomeric LRH-1 receptor that binds to NR half-sites might function together with FXR to activate gene expression.ResultsTo analyze the global pattern for LRH-1 binding and to determine whether it might associate with FXR on a whole genome-wide scale, we analyzed LRH-1 binding to the entire hepatic genome using a non-biased genome-wide ChIP-seq approach. We identified over 10,600 LRH-1 binding sites in hepatic chromatin and over 20% were located within 2 kb of the 5' end of a known mouse gene. Additionally, the results demonstrate that a significant fraction of the genome sites occupied by LRH-1 are located close to FXR binding sites revealed in our earlier study. A Gene ontology analysis revealed that genes preferentially enriched in the LRH-1/FXR overlapping gene set are related to lipid metabolism. These results demonstrate that LRH-1 recruits FXR to lipid metabolic genes. A significant fraction of FXR binding peaks also contain a nuclear receptor half-site that does not bind LRH-1 suggesting that additional monomeric nuclear receptors such as RORs and NR4As family members may also target FXR to other pathway selective genes related to other areas of metabolism such as glucose metabolism where FXR has also been shown to play an important role.ConclusionThese results document an important role for LRH-1 in hepatic metabolism through acting predominantly at proximal promoter sites and working in concert with additional nuclear receptors that bind to neighboring sites
Highlights
In a previous genome-wide analysis of FXR binding to hepatic chromatin, we noticed that an extra nuclear receptor (NR) half-site was co-enriched close to the FXR binding IR-1 elements and we provided limited support that the monomeric LRH-1 receptor that binds to NR half-sites might function together with FXR to activate gene expression
In our analysis of FXR binding to hepatic chromatin, we showed that LRH-1 could function as a partner transcription factor for FXR on a small set of target genes through binding to a nuclear receptor half-site that was co-enriched with the FXR IR-1 element on a genomewide scale [14]
Identification of the Hepatic Cistrome for LRH-1 In our previous studies of genome-wide binding for FXR, our analysis revealed that an additional nuclear receptor (NR) half-site was present in 71% of the FXR/ RXR binding IR-1 sites from our liver FXR ChIP-seq dataset [14]
Summary
In a previous genome-wide analysis of FXR binding to hepatic chromatin, we noticed that an extra nuclear receptor (NR) half-site was co-enriched close to the FXR binding IR-1 elements and we provided limited support that the monomeric LRH-1 receptor that binds to NR half-sites might function together with FXR to activate gene expression. In addition to the non-DNA binding ligand-gated coregulators, nuclear receptor activity can be influenced by the binding of other DNA binding partner proteins that can interact with the nuclear receptors to form a cis-regulatory module to enhance or repress the transcription of select target genes [3]. The liver receptor homolog-1 (LRH-1; NR5A2)) is expressed mainly in the liver, intestine, exocrine pancreas, and ovary [4,5,6] and plays a role in the regulation of bile acid, cholesterol, and steroid hormone homeostasis. It belongs to a nuclear receptor subfamily that includes steroidogenic factor 1 (SF-1; NR5A1). LRH-1 was cloned independently by several groups and it received many names, including pancreas homolog receptor 1 (PHR-1), fetoprotein transcription factor (FTF), CYP7A1 promoter binding factor (CPF), human B1 binding factor (hB1F) [7]
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