Function Annotation of Hepatic Retinoid x Receptor α Based on Genome-Wide DNA Binding and Transcriptome Profiling

Qi Zhan, Yaping Fang, Yuqi He, Hui Xin Liu, Jianwen Fang, Yu-Jui Yvonne Wan

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: Retinoid x receptor α (RXRα) is abundantly expressed in the liver and is essential for the function of other nuclear receptors. Using chromatin immunoprecipitation sequencing and mRNA profiling data generated from wild type and RXRα-null mouse livers, the current study identifies the bona-fide hepatic RXRα targets and biological pathways. In addition, based on binding and motif analysis, the molecular mechanism by which RXRα regulates hepatic genes is elucidated in a high-throughput manner. Principal Findings: Close to 80% of hepatic expressed genes were bound by RXRα, while 16% were expressed in an RXRα-dependent manner. Motif analysis predicted direct repeat with a spacer of one nucleotide as the most prevalent RXRα binding site. Many of the 500 strongest binding motifs overlapped with the binding motif of specific protein 1. Biological functional analysis of RXRα-dependent genes revealed that hepatic RXRα deficiency mainly resulted in up-regulation of steroid and cholesterol biosynthesis-related genes and down-regulation of translation- as well as anti-apoptosis-related genes. Furthermore, RXRα bound to many genes that encode nuclear receptors and their cofactors suggesting the central role of RXRα in regulating nuclear receptor-mediated pathways. Conclusions: This study establishes the relationship between RXRα DNA binding and hepatic gene expression. RXRα binds extensively to the mouse genome. However, DNA binding does not necessarily affect the basal mRNA level. In addition to metabolism, RXRα dictates the expression of genes that regulate RNA processing, translation, and protein folding illustrating the novel roles of hepatic RXRα in post-transcriptional regulation.

Original languageEnglish (US)
Article numbere50013
JournalPLoS One
Volume7
Issue number11
DOIs
StatePublished - Nov 15 2012

Fingerprint

retinoids
DNA Fingerprinting
liver function
Retinoids
Gene Expression Profiling
transcriptomics
Genes
Genome
receptors
genome
Liver
DNA
liver
Cytoplasmic and Nuclear Receptors
genes
translation (genetics)
Protein folding
Gene Expression
Functional analysis
Messenger RNA

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Function Annotation of Hepatic Retinoid x Receptor α Based on Genome-Wide DNA Binding and Transcriptome Profiling. / Zhan, Qi; Fang, Yaping; He, Yuqi; Liu, Hui Xin; Fang, Jianwen; Wan, Yu-Jui Yvonne.

In: PLoS One, Vol. 7, No. 11, e50013, 15.11.2012.

Research output: Contribution to journalArticle

Zhan, Qi ; Fang, Yaping ; He, Yuqi ; Liu, Hui Xin ; Fang, Jianwen ; Wan, Yu-Jui Yvonne. / Function Annotation of Hepatic Retinoid x Receptor α Based on Genome-Wide DNA Binding and Transcriptome Profiling. In: PLoS One. 2012 ; Vol. 7, No. 11.
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abstract = "Background: Retinoid x receptor α (RXRα) is abundantly expressed in the liver and is essential for the function of other nuclear receptors. Using chromatin immunoprecipitation sequencing and mRNA profiling data generated from wild type and RXRα-null mouse livers, the current study identifies the bona-fide hepatic RXRα targets and biological pathways. In addition, based on binding and motif analysis, the molecular mechanism by which RXRα regulates hepatic genes is elucidated in a high-throughput manner. Principal Findings: Close to 80{\%} of hepatic expressed genes were bound by RXRα, while 16{\%} were expressed in an RXRα-dependent manner. Motif analysis predicted direct repeat with a spacer of one nucleotide as the most prevalent RXRα binding site. Many of the 500 strongest binding motifs overlapped with the binding motif of specific protein 1. Biological functional analysis of RXRα-dependent genes revealed that hepatic RXRα deficiency mainly resulted in up-regulation of steroid and cholesterol biosynthesis-related genes and down-regulation of translation- as well as anti-apoptosis-related genes. Furthermore, RXRα bound to many genes that encode nuclear receptors and their cofactors suggesting the central role of RXRα in regulating nuclear receptor-mediated pathways. Conclusions: This study establishes the relationship between RXRα DNA binding and hepatic gene expression. RXRα binds extensively to the mouse genome. However, DNA binding does not necessarily affect the basal mRNA level. In addition to metabolism, RXRα dictates the expression of genes that regulate RNA processing, translation, and protein folding illustrating the novel roles of hepatic RXRα in post-transcriptional regulation.",
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