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Mol Cell. 2015 Apr 16;58(2):203-15. doi: 10.1016/j.molcel.2015.02.029. Epub 2015 Mar 26.

Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation.

Author information

1
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
2
Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
3
Ben May Department of Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
4
Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
5
Proteomics Resource Center, The Rockefeller University, New York, NY 10065, USA.
6
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA. Electronic address: alliscd@rockefeller.edu.

Abstract

Acetylation of histones at DNA regulatory elements plays a critical role in transcriptional activation. Histones are also modified by other acyl moieties, including crotonyl, yet the mechanisms that govern acetylation versus crotonylation and the functional consequences of this "choice" remain unclear. We show that the coactivator p300 has both crotonyltransferase and acetyltransferase activities, and that p300-catalyzed histone crotonylation directly stimulates transcription to a greater degree than histone acetylation. Levels of histone crotonylation are regulated by the cellular concentration of crotonyl-CoA, which can be altered through genetic and environmental perturbations. In a cell-based model of transcriptional activation, increasing or decreasing the cellular concentration of crotonyl-CoA leads to enhanced or diminished gene expression, respectively, which correlates with the levels of histone crotonylation flanking the regulatory elements of activated genes. Our findings support a general principle wherein differential histone acylation (i.e., acetylation versus crotonylation) couples cellular metabolism to the regulation of gene expression.

PMID:
25818647
PMCID:
PMC4501262
DOI:
10.1016/j.molcel.2015.02.029
[Indexed for MEDLINE]
Free PMC Article
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