Characterization of histone acylations links chromatin modifications with metabolism

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 (R 2 > 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.

Targeting immunometabolism as an anti-inflammatory strategy

“…202,203 ACLY is critical in generating the pool of acetyl CoA that is subsequently used for acetylation of histones. [204][205][206] Furthermore, it is citrategenerated acetyl-CoA that is used in acetylation of GAPDH, preventing GAPDH from binding IFNγ mRNA, making ACLY a regulator of this inflammatory cytokine. 165 Moreover, malonyl CoA, the cofactor required for the PTM malonylation described above, is also generated and regulated by components of the citrate pathway.…”

Proteomics of Long‐Lived Mammals

“…Robust MS‐based methods permit quantitation of most known combinations of acetylated or methylated histone PTM sites using methods that rely on a set of synthetic peptide standards . It is also possible to develop approaches to quantitate other known histone PTMs such as acylations …”

Transcriptional memory in skeletal muscle. Don't forget (to) exercise

“…An illustrative presentation of how metabolic activity can dynamically shape the overall chromatin landscape was recently provided by a comparative study of 11 non‐tumorigenic and tumorigenic human cell lines, revealing that the cellular rate of glycolysis appeared strikingly reflected by the global level of histone acetylation (X. S. Liu, Little, & Yuan, 2015). There is emerging evidence that glycolytic flux directly feeds into histone acetylation, and the availability of acetyl‐CoA, the preferred acetyl donor used by histone acetyltransferases (HATs), profoundly determines the abundance of histone lysine acetylation at a global scale (Cluntun et al, 2015; Simithy et al, 2017). Reciprocally, in cancer cells, global deacetylation of histones, mainly accomplished by HDACs, was found crucial to maintain intracellular pH homeostasis, mechanistically being coupled to the activity of monocarboxylate transporters that preserve physiological pH by pumping protons in a cotransport together with chromatin‐derived acetate anions out of the cell (McBrian et al, 2013).…”