Genome-wide profiling of RARα and RARβ binding site reveals the role of retinoic acid in mouse liver

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 338-365-Metabolic & Stress Receptors in Energy Homeostasis
Basic/Translational
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-365
Yanliu Lu*1, Qi Zhan2, Yuqi He1 and Yu-Jui Yvonne Wan1
1Sch of Med Univ of California, D, Sacramento, CA, 2Guangzhou First Municipal People’s Hospital, Guangzhou, China
Retinoic acid (RA) is the biological active form of vitamin A that is stored in the liver. RA binds to retinoic acid receptor (RAR) α and β and their dimeric partner retinoid x receptor (RXR) α. However, the role of RARα and β in the liver is not clear. The current study identifies genome-wide RARα and RARβ targets and their biological processes in response to RA treatment in mice. Chromatin immunoprecipitation followed by sequencing data showed that RARα and RXRα bound to the mouse genome extensively; there were 10,611 and 8,071 genes bound by RARα and RXRα, respectively. Forty-five percent of the RARα binding genes also contained RXRα binding sites in the same location. In contrast, only 3,200 genes were bound by RARβ and 50% of them had overlapping RXRα binding sites in the same location. RXRα forms dimers with many nuclear receptors. However, 62% of RXRα-bound genes had already been bound by RARα or β suggesting the two RARs might be major partners of RXRα under  normal biological condition. After RA treatment (150 mg/kg diet, 1 day), the number of RARα-bound genes barely  changed; whereas, there was a substantial increase in RARβ-bound genes (228%). Close to 80% of RXRα bound genes were also bound by either RARα or β suggesting that RA treatment could deactivate many other pathways regulated by RXRα and its partners such as FXR and LXR. RA-induced binding peaks were mainly located either upstream (<10 Kb from the transcriptional start site) to a gene or within genes. More than 70% of the RARα- and RARβ-bound genes had detectable mRNA level in mouse livers suggesting their role in regulating liver function. Biological functions of the genes bound by the heterodimer of RXRα and RARα or β were different from those bound by RARs but not RXRα. The genes bound by RXRα/RAR tend to have roles in metabolic processes of fatty acid, steroid, and cholesterol while genes bound by RARα or β, but not by RXRα, mainly  take part in cell cycle and RNA processing. RA treatment induced extra binding of RXRα/RARβ on 2,274 genes. Many of those genes are involved in oxidation/reduction and protein localization and transport. Thus, mediated via RARα and β, RA has profound effect in regulating liver gene expression and function at the transcriptional and post-transcriptional levels.

Nothing to Disclose: YL, QZ, YH, YJYW

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This study is supported by grants funded by National Institutes of Health DK092100 and CA53596.
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