Intracellular Crotonyl-CoA Stimulates Transcription through p300-Catalyzed Histone Crotonylation
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SUMMARY 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.
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Histone crotonylation is catalyzed by HATs, which add a crotonyl group from crotonyl-CoA to histone amino acid residues, while HDACs 1/2/3 and sirtuin 1/2/3 act as decrotonylases.
“histone crotonylation is catalyzed by HATs, which add a crotonyl group from crotonyl-coenzyme A (CoA) to amino acid residues of histones,111 while HDACs 1/2/3 and sirtuin 1/2/3, act as decrotonylases.180–182”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [111]
Histone crotonylation occurs at promoters or enhancers of actively transcribed genes and plays a role in spermatogenesis.
“Histone crotonylation was previously shown to occur at the promoters or enhancers of gens that are actively transcribed, and play a role in spermatogenesis.111,179”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [111]
Deposition of crotonyl marks on select histone tail residues activates gene expression more potently than acetyl marks.
“Notably, deposition of crotonyl marks on select amino acid residues within histone tails was found to activate gene expression even more potently than acetyl marks (Sabari et al., 2015).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Sabari et al., 2015
p300 histone acetyltransferase utilizes crotonyl-CoA as substrate.
“In addition to acetyl-CoA, a p300 histone acetyltransferase has recently been shown to utilize crotonyl-CoA as a substrate as well.”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Sabari et al., 2015
Both lysine acetylation and lysine crotonylation share p300 as a common writer.
“Both Lys-ac and Lys-cr share a common ‘writer’ in the acyltransferase and co-activator protein, p3009.”
From Histone deacetylase (HDAC) 1 and 2 complexes regulate both histone acetylation and crotonylation in vivo (2018) · cites this paper as [9]
Histone lysine crotonylation is associated with active chromatin and overlaps with known sites of lysine acetylation.
“A number of functional studies have concentrated on histone lysine-crotonylation (Lys-cr) which is associated with active chromatin and overlaps with known sites of lysine-acetylation (Lys-ac)3,9.”
From Histone deacetylase (HDAC) 1 and 2 complexes regulate both histone acetylation and crotonylation in vivo (2018) · cites this paper as [9]
H3K18cr levels peak in the vicinity of transcription start sites and significantly overlap with H3K18ac.
“In line with previous findings9, we observed that H3K18cr levels peak in the vicinity of transcription start sites (TSS) with a significant overlap with H3K18ac (Fig. 4A).”
From Histone deacetylase (HDAC) 1 and 2 complexes regulate both histone acetylation and crotonylation in vivo (2018) · cites this paper as [9]
Histone crotonylation plays a role in active gene expression.
“consistent with a role for histone crotonylation in active gene expression9,39.”
From Histone deacetylase (HDAC) 1 and 2 complexes regulate both histone acetylation and crotonylation in vivo (2018) · cites this paper as [9]
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- Authors
- Sabari, B. R., Tang, Z., Huang, H., Yong-Gonzalez, V., Molina, H., Kong, H. E., Dai, L., Shimada, M., Cross, J. R., Zhao, Y., Roeder, R. G., & Allis, C. D.
- Affiliations
- Rockefeller University (US)
- University of Chicago (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Allis, C. David
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 58
- Issue
- 2
- Pages
- 203-215
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC5808432
- OpenAlex
- W1987909353
- Semantic Scholar
- 22f520def5d1b5f37b729a646c696d55ae746f9b
- Cited by
- 659
- References
- 24
- Citations by year
- 2026: 70 · 2025: 81 · 2024: 75 · 2023: 69 · 2022: 63 · 2021: 85 · 2020: 48 · 2019: 41 · 2018: 41 · 2017: 43 · 2016: 30 · 2015: 11
- FWCI
- 18.08
- Type
- journal article
- Language
- en
- Update notices
- erratum (2018-02-01)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA129325, U24CA160036, R01CA204639)
- National Institute of General Medical Sciences (R01GM040922, R01GM105933)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK071900)
- National Center for Research Resources (U54RR020839)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- histone crotonylation, histone acetylation, P300, crotonyl-CoA, transcriptional activation, transcriptional coactivator, gene expression regulation, cellular metabolism, histone modifications
- MeSH terms
- Acetate-CoA Ligase, Acetylation, Acyl Coenzyme A, Cell Line, Cell-Free System, HeLa Cells, Histones, Humans, Lipopolysaccharides, Macrophages, Molecular Sequence Data, RNA, Messenger, Transcriptional Activation, E1A-Associated p300 Protein, HEK293 Cells
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