Our research provides an approach to synthetically modulating histone posttranslational modifications without relying on endogenous enzymes. We have developed an artificial catalyst system comprising nucleosome-binding catalysts and acyl donors. The catalyst system preferentially acylates lysines on histone tails and modulates chromatin structure similarly to histone acetyltransferases. Our system can be a useful tool for studying chromatin-modification enzymes as well as the functions of histone acylations.

A chemical catalyst system enabling high-yielding and comprehensive lysine acetylation of nucleosomal histones was developed as an epigenetics tool.

Selective methods for introducing protein post-translational modifications (PTMs) within living cells have proven valuable for interrogating their biological function. In contrast to enzymatic methods, abiotic catalysis should offer access to diverse and new-to-nature PTMs. Herein, we report the boronate-assisted hydroxamic acid (BAHA) catalyst system, which comprises a protein ligand, a hydroxamic acid Lewis base, and a diol moiety. In concert with a boronic acid-bearing acyl donor, our catalyst leverages a local molarity effect to promote acyl transfer to a target lysine residue. Our catalyst system employs micromolar reagent concentrations and affords minimal off-target protein reactivity. Critically, BAHA is resistant to glutathione, a metabolite which has hampered many efforts toward abiotic chemistry within living cells. To showcase this methodology, we installed a variety of acyl groups in E. coli dihydrofolate reductase expressed within human cells. Our results further establish the well-known boronic acid− diol complexation as a bona f ide bio-orthogonal reaction with applications in chemical biology and in-cell catalysis.

Post-translational modifications (PTMs) of proteins, e.g., epigenetic acetylation of lysine residues in histones, are crucial to cellular functions and related to diseases. Chemical tools to directly introducing epigenetic lysine acetylation hold promise for elucidating the PTM’s functions and treating diseases. Although several chemical catalysts introducing protein acetylation in live cells were reported, there is no precedent promoting in-cell acetylation of epigenetically important but often low-reactive histone proteins using endogenous acetyl-CoA, as histone acetyltransferases (HATs) do. Herein, we developed a chemical catalyst mBnA enabling selective in-cell histone lysine acylation (H2BK120ac) using endogenous acyl-CoA as a sole acyl donor. A hydroxamic acid of proper electronic characteristics as a nucleophilic catalytic site combined with a thiol-thioester exchange process enabled mBnA to activate low concentration of acyl-CoAs in cells, promoting histone lysine acylations (acetylation and malonylation). This chemical catalyst will be a small-molecule surrogate to HAT and thus a unique tool to synthetic epigenetics.