We have reported 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). Viral infection triggers innate immune signaling, which in turn induces interferon-β (IFN-β) production to establish innate antiviral immunity. Previous studies showed that Gcn5 (Kat2a), a histone acetyltransferase (HAT) with partial functional redundancy with PCAF (Kat2b), and Gcn5/PCAF-mediated histone H3K9 acetylation (H3K9ac) are enriched on the active IFNB gene promoter. However, whether Gcn5/PCAF and H3K9ac regulate IFN-β production is unknown. In a recent study, we show that Gcn5/PCAF-mediated H3K9ac correlates well with, but is surprisingly dispensable for, the expression of endogenous IFNB and the vast majority of active genes in fibroblasts. Instead, Gcn5/PCAF repress IFN-β production and innate antiviral immunity in several cell types in a HAT-independent and non-transcriptional manner: by inhibiting the innate immune signaling kinase TBK1 in the cytoplasm. Our results thus identify Gcn5 and PCAF as negative regulators of IFN-β production and innate immune signaling (Jin Q. et al., EMBO Rep, 2014).

Project Start
Project End
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Budget End
Support Year
9
Fiscal Year
2015
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Indirect Cost
Name
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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