Abstract
Chromatin remodeling and histone modifications play essential roles in the regulation of gene activation or silencing in physiologic and disease processes. Among the histone modifying enzymes, histone deacetylases (HDACs) and lysine specific demethylase 1 (LSD1) have been shown to be critical in transcriptional regulation and are considered drug targets in cancer and other diseases. The CoREST complex contains HDAC1 (or HDAC2) and LSD1 but the interplay between subunits of this complex and their interactions with nucleosomes is poorly understood. We have employed engineered sortase to generated histone H3 containing post‐translational modifications (PTMs) that ligates H3 N‐tail depsipeptides and globular histone H3 with excellent conversions and all native sequence. These semisynthetic histone H3s possessing various combinations of H3K4‐dimethyl and N‐tail Lys acetylation marks were incorporated into reconstituted mononucleosomes and investigated as substrates with the purified core CoREST complex. These experiments revealed an interdependence of particular PTMs in CoREST processing and regioselective CoREST deacetylation. In addition, we prepared nucleosomes containing N‐propargyl and hydroxamic acid Lys analogs as probes of CoREST interaction. These unnatural warheads enhanced the stability of CoREST complex‐nucleosome complexes which should facilitate biophyiscal characterization.Support or Funding InformationNIHThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Published Version
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