Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation.
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.
Nuclear Receptor Biology Section, CEB, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Qihuang
Q
Jin
Li-Rong
LR
Yu
Lifeng
L
Wang
Zhijing
Z
Zhang
Lawryn H
LH
Kasper
Ji-Eun
JE
Lee
Chaochen
C
Wang
Paul K
PK
Brindle
Sharon Y R
SY
Dent
Kai
K
Ge
D000107:Acetylation; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006657:Histones / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D047494:PPAR delta / Q000819:agonists / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013379:Substrate Specificity; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D050881:E1A-Associated p300 Protein; D006657:Histones; D047494:PPAR delta; D013844:Thiazoles; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C474772:ANGPTL4 protein, human; C425931:GW 501516; C494360:EP300 protein, human