Journal Article

Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation

Lee, Ji‐Eun, Yu, Li‐Rong, Kasper, Lawryn H, Jin, Qihuang, Wang, Chaochen, Brindle, Paul K, Zhang, Zhijing, Dent, Sharon Y R, Wang, Lifeng, Ge, Kai

2011

Overview

Histone acetyltransferases (HATs) GCN5 and PCAF (GCN5/PCAF) and CBP and p300 (CBP/p300) are transcription co‐activators. However, how these two distinct families of HATs regulate gene activation remains unclear. Here, we show deletion of GCN5/PCAF in cells specifically and dramatically reduces acetylation on histone H3K9 (H3K9ac) while deletion of CBP/p300 specifically and dramatically reduces acetylations on H3K18 and H3K27 (H3K18/27ac). A ligand for nuclear receptor (NR) PPARδ induces sequential enrichment of H3K18/27ac, RNA polymerase II (Pol II) and H3K9ac on PPARδ target gene Angptl4 promoter, which correlates with a robust Angptl4 expression. Inhibiting transcription elongation blocks ligand‐induced H3K9ac, but not H3K18/27ac, on the Angptl4 promoter. Finally, we show GCN5/PCAF and GCN5/PCAF‐mediated H3K9ac correlate with, but are surprisingly dispensable for, NR target gene activation. In contrast, CBP/p300 and their HAT activities are essential for ligand‐induced Pol II recruitment on, and activation of, NR target genes. 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 NR‐dependent transcription. In general, histone acetylation correlates with gene activation; however, it is not clear if it is a cause or consequence of increased transcription. Here, the related histone acetyltransferases CBP and p300, which acetylate H3K18 and H3K27, are shown to be required for the induction of PPARδ target genes, while GCN5/PCAF‐mediated H3K9 acetylation is dispensable.

• Publisher: John Wiley & Sons, Ltd,Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: Acetylation / Angiopoietin-Like Protein 4 / Angiopoietins - genetics / Animals / Blotting, Western / CBP and p300 / Cellular biology / Chromatin Immunoprecipitation / E1A-Associated p300 Protein - genetics / E1A-Associated p300 Protein - metabolism / GCN5 and PCAF / Gene expression / Gene Knockout Techniques / histone acetylation / Histones - metabolism / Humans / Mass Spectrometry / Mice / Molecular biology / nuclear receptor / p300-CBP Transcription Factors - genetics / p300-CBP Transcription Factors - metabolism / PPAR delta - agonists / PPAR delta - metabolism / Promoter Regions, Genetic - genetics / Reverse Transcriptase Polymerase Chain Reaction / RNA polymerase / Substrate Specificity / Substrates / Thiazoles - metabolism / Thiazoles - pharmacology / Transcriptional Activation - drug effects / Transcriptional Activation - physiology