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Post-translational modifications

Crotonylation versus acetylation

Credit: NPG/Vicky Summersby

Histone lysine acetylation at DNA regulatory elements promotes transcriptional activation. Other related histone modifications — termed acylations — have been identified in recent years, but their functional significance remains unclear. Allis and colleagues now report that p300-catalysed histone crotonylation is a more potent transcriptional activator than histone acetylation. They also find that whether histone lysines are crotonylated or acetylated depends on the relative intracellular concentrations of crotonyl-CoA and acetyl-CoA, thereby linking cellular metabolism to gene expression.

The authors purified a histone crotonyltransferase (HCT) activity from HeLa cell nuclear extracts to identify enzymes capable of catalysing histone crotonylation. Surprisingly, the HCT activity co-purified with histone acetyltransferase (HAT) activity. Mass spectrometry analysis revealed that the most abundant protein in the fraction that contained both activities was the HAT and transcriptional co-activator p300. The authors confirmed that p300 also has an intrinsic HCT activity in vitro and that it regulates histone H3 lysine 18 crotonylation (H3K18Cr) and H3K18 acetylation (H3K18Ac) in cells.

Next, the authors performed a cell-free transcription assay in the presence of either acetyl-CoA or crotonyl-CoA, which are the cofactors that donate acetyl and crotonyl, respectively. Interestingly, transcription was stimulated to a greater extent in crotonyl-CoA-containing reactions (in which p300-catalysed crotonylation is favoured over acetylation) than in acetyl-CoA-containing reactions. Moreover, the authors confirmed that transcription was stimulated by p300-dependent modification of H3 lysine residues. The authors went on to show that, in mammalian cells, the relative concentrations of crotonyl-CoA and acetyl-CoA, which compete for p300, determine the nature of p300 reaction products. Furthermore, they found that the cellular concentrations of crotonyl-CoA are generally low and that adding crotonate to cell cultures, or reducing the intracellular levels of acetyl-CoA, leads to an increase in histone crotonylation through the direct production of crotonyl-CoA.

To analyse the involvement of H3K18Cr in gene activation in cells, the authors used a macrophage cell line in which they induced an inflammatory response that involves the activation of a well-characterized transcriptional programme. RNA-seq and ChIP–seq data revealed that H3K18Ac and H3K18Cr both localize to transcriptional start sites and regulatory elements of activated genes, strongly suggesting that histone crotonylation has a role in transcriptional activation in vivo. Next, the authors increased the cellular concentration of crotonyl-CoA, which led to a dose-dependent increase in H3K18Cr at the promoters of genes that were activated by the inflammatory response and a concomitant decrease in H3K18Ac. Importantly, expression of these genes was positively correlated with crotonate concentrations, indicating that the balance between histone crotonylation and histone acetylation has a functional consequence for gene expression. Last, knockdown of the metabolic enzyme acetyl-CoA synthetase 2, which reduces crotonyl-CoA levels, led to a decrease in H3K18Cr in the aforementioned gene promoters and corresponding lower levels of gene expression.

“These findings provide another link between metabolism, chromatin and gene expression”

This study shows that p300 has HCT activity and that differential acylation (crotonylation versus acetylation) of histone lysines, catalysed by p300, is regulated metabolically by cellular levels of crotonyl-CoA and acetyl-CoA and affects gene expression. These findings provide another link between metabolism, chromatin and gene expression. However, it remains to be determined how, mechanistically, histone crotonylation functions as a strong transcriptional activator.

References

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    Sabari, B. R. et al. Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Mol. Cell http://dx.doi.org/10.1016/j.molcel.2015.02.029 (2015)

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Choudhary, C. et al. The growing landscape of lysine acetylation links metabolism and cell signalling. Nature Rev. Mol. Cell Biol. 15, 536–550 (2014)

Verdin, E. & Ott, M. 50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond. Nature Rev. Mol. Cell Biol. 16, 258–264 (2015)

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Baumann, K. Crotonylation versus acetylation. Nat Rev Mol Cell Biol 16, 265 (2015). https://doi.org/10.1038/nrm3992

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