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Abstract
Post-translational modifications of histones are critical to a plethora of cellular processes. A key histone modification, histone lysine acetylation, is well orchestrated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs function as epigenetic writers by transferring an acetyl group from acetyl-coenzyme A (Ac-CoA) to the ε-amino groups of lysine residues to form ε-N-acetyllysine in a histone or non-histone substrate. Despite the intricate regulation, HAT overexpression has been correlated with disease states, such as cancer and inflammatory diseases. HAT inhibitors, therefore, are emerging as promising therapeutics to tune histone acetylation. In this work, we examined structure-activity relationships between acyl-CoAs and HATs and observed correlation between acyl chain length and inhibitory potency. Based on our findings, we synthesized several CoA derivatives, and evaluated their biological activities in vitro and in cells. In particular, a dimethylaminonaphthalene-CoA derivative A433-CoA was found to be one of the most potent inhibitors for the HAT p300. This selective HAT inhibitor will be a useful biological tool to investigate the role of p300-related pathways and may serve as a lead for development of novel anti-neoplastic therapeutics. In addition, we identified a novel histone modification, lysine isobutyrylation, which gains more in-depth knowledge of lysine acylations especially lysine butyrylation. We also found that both butyrate and isobutyrate could inhibit HDAC activity, increase levels of histone acetylation and therefore influence global gene transcription. We hope that our work can shed light on PTMs and epigenetics, providing clues for studies in epigenetics.