PPARdelta is a member of the PPAR family of nuclear receptors and is ubiquitously expressed. Activation of PPARdelta promotes fat burning. Highly specific synthetic PPARdelta ligands (agonists), such as GW501516 (GW), are promising drug candidates for obesity and diabetes. Endogenous PPARdelta is abundantly expressed in mouse embryonic fibroblasts (MEFs) but associates with histone deacetylases and behaves as a transcriptional repressor in the absence of ligand. Upon ligand treatment, endogenous PPARdelta switches from a repressor to an activator, which leads to a robust activation of target genes such as Angptl4. We are using the GW-induced Angptl4 expression in MEFs as a model system to investigate the roles of histone acetyltransferases GCN5/PCAF, CBP/p300, and associated histone acetylations in regulating expression of endogenous nuclear receptor target genes. We report that the two pairs of histone acetyltransferases (HATs), GCN5/PCAF and CBP/p300, are specifically required for H3K9 acetylation (H3K9ac) and H3K18/27 acetylation (H3K18/27ac), respectively, in cells. Further, we show that CBP/p300 and their HAT activities are essential, while GCN5/PCAF and associated H3K9ac are dispensable, for ligand-induced nuclear receptor target gene expression. These results highlight the substrate and site specificities of HATs in cells, demonstrate the distinct roles of GCN5/PCAF- and CBP/p300-mediated histone acetylations in gene activation, and suggest an important role of CBP/p300-mediated H3K18/27ac in nuclear receptor target gene expression (Jin Q. et al., EMBO J, 2011). Using ligand-induced PPARdelta target gene expression in MEFs as a robust model system, we will continue to study epigenetic regulation of NR target gene expression. The results will be verified using other NRs including PPARgamma. 1st, we will use MEFs derived from our collection of conditional KO mice to investigate the roles of site-specific histone methylations in NR target gene expression. 2nd, we will investigate how CBP/p300-mediated H3K18/27ac regulate NR target gene expression. We hypothesize that CBP/p300-mediated H3K18/27ac may be recognized by yet to be identified effector proteins, which recruit Pol II to initiate transcription. We will use affinity purification to isolate and determine the identities of the effector proteins. 3rd, we will investigate the roles of other epigenetic mechanisms, such as chromatin remodeling, and their functional cooperation with histone modifications, in ligand-induced NR target gene expression.

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8
Fiscal Year
2014
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U.S. National Inst Diabetes/Digst/Kidney
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Park, Young-Kwon; Wang, Limin; Giampietro, Anne et al. (2017) Distinct Roles of Transcription Factors KLF4, Krox20, and Peroxisome Proliferator-Activated Receptor ? in Adipogenesis. Mol Cell Biol 37:
Park, Young-Kwon; Ge, Kai (2017) Glucocorticoid Receptor Accelerates, but Is Dispensable for, Adipogenesis. Mol Cell Biol 37:
Jang, Younghoon; Wang, Chaochen; Zhuang, Lenan et al. (2017) H3K4 Methyltransferase Activity Is Required for MLL4 Protein Stability. J Mol Biol 429:2046-2054
Jin, Qihuang; Wang, Chaochen; Kuang, Xianghong et al. (2014) Gcn5 and PCAF regulate PPAR? and Prdm16 expression to facilitate brown adipogenesis. Mol Cell Biol 34:3746-53
Kumar, Amit; Lualdi, Margaret; Loncarek, Jadranka et al. (2014) Loss of function of mouse Pax-Interacting Protein 1-associated glutamate rich protein 1a (Pagr1a) leads to reduced Bmp2 expression and defects in chorion and amnion development. Dev Dyn 243:937-47
Xu, Shiliyang; Grullon, Sean; Ge, Kai et al. (2014) Spatial clustering for identification of ChIP-enriched regions (SICER) to map regions of histone methylation patterns in embryonic stem cells. Methods Mol Biol 1150:97-111
Lee, Ji-Eun; Ge, Kai (2014) Transcriptional and epigenetic regulation of PPAR? expression during adipogenesis. Cell Biosci 4:29
Jin, Qihuang; Zhuang, Lenan; Lai, Binbin et al. (2014) Gcn5 and PCAF negatively regulate interferon-? production through HAT-independent inhibition of TBK1. EMBO Rep 15:1192-201
Lee, Ji-Eun; Wang, Chaochen; Xu, Shiliyang et al. (2013) H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. Elife 2:e01503
Park, Jun Hong; Kang, Hong Jun; Kang, Soo Im et al. (2013) A multifunctional protein, EWS, is essential for early brown fat lineage determination. Dev Cell 26:393-404

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