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

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

Research output: Contribution to journalArticle

367 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)249-262
Number of pages14
JournalEMBO Journal
Volume30
Issue number2
DOIs
StatePublished - Jan 19 2011

Fingerprint

Cytoplasmic and Nuclear Receptors
Histone Acetyltransferases
Transcriptional Activation
Acetylation
Genes
Transcription
Peroxisome Proliferator-Activated Receptors
Chemical activation
Ligands
Histones
RNA Polymerase II
Substrate Specificity
Elongation
Substrates

Keywords

  • CBP and p300
  • GCN5 and PCAF
  • histone acetylation
  • nuclear receptor

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation. / Jin, Qihuang; Yu, Li Rong; Wang, Lifeng; Zhang, Zhijing; Kasper, Lawryn H.; Lee, Ji Eun; Wang, Chaochen; Brindle, Paul K.; Dent, Sharon Y R; Ge, Kai.

In: EMBO Journal, Vol. 30, No. 2, 19.01.2011, p. 249-262.

Research output: Contribution to journalArticle

Jin, Q, Yu, LR, Wang, L, Zhang, Z, Kasper, LH, Lee, JE, Wang, C, Brindle, PK, Dent, SYR & Ge, K 2011, 'Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation', EMBO Journal, vol. 30, no. 2, pp. 249-262. https://doi.org/10.1038/emboj.2010.318
Jin, Qihuang ; Yu, Li Rong ; Wang, Lifeng ; Zhang, Zhijing ; Kasper, Lawryn H. ; Lee, Ji Eun ; Wang, Chaochen ; Brindle, Paul K. ; Dent, Sharon Y R ; Ge, Kai. / Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation. In: EMBO Journal. 2011 ; Vol. 30, No. 2. pp. 249-262.
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T1 - Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation

AU - Jin, Qihuang

AU - Yu, Li Rong

AU - Wang, Lifeng

AU - Zhang, Zhijing

AU - Kasper, Lawryn H.

AU - Lee, Ji Eun

AU - Wang, Chaochen

AU - Brindle, Paul K.

AU - Dent, Sharon Y R

AU - Ge, Kai

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N2 - 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.

AB - 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.

KW - CBP and p300

KW - GCN5 and PCAF

KW - histone acetylation

KW - nuclear receptor

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