Intracellular Crotonyl-CoA Stimulates Transcription through p300-Catalyzed Histone Crotonylation

Sabari, Benjamin R.; Tang, Zhanyun; Huang, He; Yong-Gonzalez, Vladimir; Molina, Henrik; Kong, Ha Eun; Dai, Lunzhi; Shimada, Miho; Cross, Justin R.; Zhao, Yingming; Roeder, Robert G.; Allis, C. David

doi:10.1016/j.molcel.2015.02.029

Cited by 479 publications

(660 citation statements)

References 24 publications

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“…Histone crotonylation, for example, has been shown to impact gene regulation and is sensitive to crotonyl-CoA levels generated in part by ACSS2 (38). Both crotonyl-CoA and ACSS2 levels were suppressed by HFD in WAT; further investigation into the impact of diet on histone crotonylation may thus point toward new mechanisms of gene regulation in response to diet.…”

Section: Journal Of Biological Chemistry 3317mentioning

confidence: 99%

Impact of a High-fat Diet on Tissue Acyl-CoA and Histone Acetylation Levels

Carrer

Parris

Trefely

et al. 2017

Journal of Biological Chemistry

140

116

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Edited by John M. DenuCellular metabolism dynamically regulates the epigenome via availability of the metabolite substrates of chromatin-modifying enzymes. The impact of diet on the metabolism-epigenome axis is poorly understood but could alter gene expression and influence metabolic health. ATP citrate-lyase produces acetyl-CoA in the nucleus and cytosol and regulates histone acetylation levels in many cell types. Consumption of a high-fat diet (HFD) results in suppression of ATP citrate-lyase levels in tissues such as adipose and liver, but the impact of diet on acetyl-CoA and histone acetylation in these tissues remains unknown. Here we examined the effects of HFD on levels of acyl-CoAs and histone acetylation in mouse white adipose tissue (WAT), liver, and pancreas. We report that mice consuming a HFD have reduced levels of acetyl-CoA and/or acetyl-CoA:CoA ratio in these tissues. In WAT and the pancreas, HFD also impacted the levels of histone acetylation; in particular, histone H3 lysine 23 acetylation was lower in HFD-fed mice. Genetic deletion of Acly in cultured adipocytes also suppressed acetyl-CoA and histone acetylation levels. In the liver, no significant effects on histone acetylation were observed with a HFD despite lower acetyl-CoA levels. Intriguingly, acetylation of several histone lysines correlated with the acetyl-CoA: (iso)butyryl-CoA ratio in liver. ButyrylCoA and isobutyryl-CoA interacted with the acetyltransferase P300/CBP-associated factor (PCAF) in liver lysates and inhibited its activity in vitro. This study thus provides evidence that diet can impact tissue acyl-CoA and histone acetylation levels and that acetyl-CoA abundance correlates with acetylation of specific histone lysines in WAT but not in the liver.

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Section: Journal Of Biological Chemistry 3317mentioning

confidence: 99%

Impact of a High-fat Diet on Tissue Acyl-CoA and Histone Acetylation Levels

Carrer

Parris

Trefely

et al. 2017

Journal of Biological Chemistry

140

116

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“…To conduct this meta-analysis, we made use of published genome-wide studies of these histone PTMs to calculate nucleosome-based Spearman correlations with Sas3 and Yng1 ( Figure 2A and Table S4) . Since crotonylation has not been mapped in S. cerevisiae, but colocalizes with acetylation in mammalian cells (Sabari et al 2015), we used H3K9ac as a proxy for H3K9cr. To our surprise, H3K9ac did not correlate with Sas3 or Yng1, which suggests that despite Taf14 binding in vitro, it does not function in NuA3 recruitment in vivo.…”

Section: Nua3 Is Primarily Bound To Midgene Regions Of Actively Transmentioning

confidence: 99%

Histone H3K4 and H3K36 Methylation Independently Recruit the NuA3 Histone Acetyltransferase in Saccharomyces cerevisiae

et al. 2017

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Histone post-translational modifications (PTMs) alter chromatin structure by promoting the interaction of chromatinmodifying complexes with nucleosomes. The majority of chromatin-modifying complexes contain multiple domains that preferentially interact with modified histones, leading to speculation that these domains function in concert to target nucleosomes with distinct combinations of histone PTMs. In Saccharomyces cerevisiae, the NuA3 histone acetyltransferase complex contains three domains, the PHD finger in Yng1, the PWWP domain in Pdp3, and the YEATS domain in Taf14; which in vitro bind to H3K4 methylation, H3K36 methylation, and acetylated and crotonylated H3K9, respectively. While the in vitro binding has been well characterized, the relative in vivo contributions of these histone PTMs in targeting NuA3 is unknown. Here, through genome-wide colocalization and by mutational interrogation, we demonstrate that the PHD finger of Yng1, and the PWWP domain of Pdp3 independently target NuA3 to H3K4 and H3K36 methylated chromatin, respectively. In contrast, we find no evidence to support the YEATS domain of Taf14 functioning in NuA3 recruitment. Collectively our results suggest that the presence of multiple histone PTM binding domains within NuA3, rather than restricting it to nucleosomes containing distinct combinations of histone PTMs, can serve to increase the range of nucleosomes bound by the complex. Interestingly, however, the simple presence of NuA3 is insufficient to ensure acetylation of the associated nucleosomes, suggesting a secondary level of acetylation regulation that does not involve control of HAT-nucleosome interactions.

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“…Members of three different KAT families catalyze lysine acylation in vitro: p300/CBP catalyzes propionylation, butyrylation, and crotonylation of histones and p53 (Chen et al, 2007;Sabari et al, 2015), yeast Esa1, a member of the MYST family of acetyltransferases, catalyzes propionylation of histone H4 peptides (Berndsen et al, 2007), and human P/CAF, which is closely related by sequence homology to Gcn5, catalyzes propionylation of histone H3 peptides (Leemhuis et al, 2008). Some KATs are clearly promiscuous with regards to acyl chain identity, but the mechanisms employed by acyltransferases to discriminate between different acyl-CoA molecules are still largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Structural basis for acyl group discrimination by human Gcn5L2

Ringel

Wolberger

2016

Preprint

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Gcn5 is a conserved acetyltransferase that regulates transcription by acetylating the Nterminal tails of histones. Motivated by recent studies identifying a chemically diverse array of lysine acyl modifications in vivo, we examined the acyl chain specificity of the acetyltransferase, human Gcn5 (Gcn5L2). Whereas Gcn5L2 robustly catalyzes lysine acetylation, the acyltransferase activity of Gcn5L2 gets progressively weaker with increasing acyl chain length. To understand how Gcn5 discriminates between different acyl-CoA molecules, we determined structures of the catalytic domain of human Gcn5L2 bound to propionyl-CoA and butyryl-CoA. Although the active site of Gcn5L2 can accommodate propionyl-CoA and butyryl-CoA without major structural rearrangements, butyryl-CoA adopts a conformation incompatible with catalysis that obstructs the path of the incoming lysine residue and acts as a competitive inhibitor for Gcn5L2 versus acetyl-CoA. These structures demonstrate how Gcn5L2 discriminates between acyl chain donors and explain why Gcn5L2 has weak activity for acyl moieties that are larger than an acetyl group.

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Intracellular Crotonyl-CoA Stimulates Transcription through p300-Catalyzed Histone Crotonylation

Cited by 479 publications

References 24 publications

Impact of a High-fat Diet on Tissue Acyl-CoA and Histone Acetylation Levels

Impact of a High-fat Diet on Tissue Acyl-CoA and Histone Acetylation Levels

Histone H3K4 and H3K36 Methylation Independently Recruit the NuA3 Histone Acetyltransferase in Saccharomyces cerevisiae

Structural basis for acyl group discrimination by human Gcn5L2

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