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Abstract
Over the last decade, numerous histone acyl post-translational modifications (acyl-PTMs) have been discovered, of which the functional significance is still under intense study. Here, we use high-resolution mass spectrometry to accurately quantify eight acyl-PTMs in vivo and after in vitro enzymatic assays. We assess the ability of seven histone acetyltransferases (HATs) to catalyze acylations on histones in vitro using short-chain acyl-CoA donors, proving that they are less efficient towards larger acyl-CoAs. We also observe that acyl-CoAs can acylate histones through non-enzymatic mechanisms. Using integrated metabolomic and proteomic approaches, we achieve high correlation (R2 > 0.99) between the abundance of acyl-CoAs and their corresponding acyl-PTMs. Moreover, we observe a dose-dependent increase in histone acyl-PTM abundances in response to acyl-CoA supplementation in in nucleo reactions. This study represents a comprehensive profiling of scarcely investigated low-abundance histone marks, revealing that concentrations of acyl-CoAs affect histone acyl-PTM abundances by both enzymatic and non-enzymatic mechanisms.
Highlights
Over the last decade, numerous histone acyl post-translational modifications have been discovered, of which the functional significance is still under intense study
They were less efficient catalyzing the acylation of histones with charged, branched or planar acyl-CoA cofactors. Even though these acyl donors are structurally similar to acetyl-CoA, the universal cofactor of histone acetyltransferases (HATs), our data showed that the ability of enzymes to utilize other cofactors largely depended on the size of the acyl group, which is in close agreement with recent data demonstrating the structural incompatibility of the active sites of p300 and GCN5 with long-chain acyl donors[32,33]
The data showed a similar trend in which the preference for a cofactor different from acetyl-CoA was inversely proportional to the molecular weight of the competing donor, except for crotonyl-CoA, which, unlike the other acyl groups, possesses an unsaturated moiety that seems to render its use by most HATs unfavorable
Summary
Numerous histone acyl post-translational modifications (acyl-PTMs) have been discovered, of which the functional significance is still under intense study. A growing number of lysine modifications chemically related to acetylation (propionylation, malonylation, crotonylation, butyrylation, succinylation, glutarylation, 2-hydroxyisobutyrylation and β-hydroxybutyrylation) have been identified on histones using mass spectrometry (MS)-based proteomic approaches[8,9,10,11,12,13,14] These findings have raised numerous questions regarding their functional significance, possible implications in metabolic pathways and the existence of a b. These studies suggest that newly identified histone acylPTMs may have unique or similar roles to acetylation in transcriptional activation Such observations are supported by several reports showing that SIRT5, a member of the class III HDACs can preferentially remove acidic acyl modifications, including malonyl[22], succinyl[22,23] and glutaryl[13], whereas propionyl, crotonyl and butyryl marks can be removed by various other sirtuins[24]. It is still open to debate whether these modifications are strategically positioned on the chromatin by enzymes or whether their presence is instead the result of non-enzymatic chemical reactivity
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