Lysine-14 acetylation of histone H3 in chromatin confers resistance to the deacetylase and demethylase activities of an epigenetic silencing complex.

Additional files Supplementary files . Transparent reporting form DOI: https://doi.org/10.7554/eLife.37231.023 Data availability All data generated or analyses during this study have been deposited in Dryad. The following dataset was generated: Author(s) Year Dataset title Dataset URL Database, license, and accessibility information Wu M, Dawn H, Jay H Kalin, Yun Song, John WR Schwabe, Philip A Cole 2018 Data from: Lysine-14 acetylation of histone H3 in chromatin confers resistance to the deacetylase and demethylase activities of an epigenetic silencing complex http://dx.doi.org/10.5061/dryad.413tm83 Available at Dryad Digital Repository under a CC0 Public Domain Dedication ; The core CoREST complex (LHC) contains histone deacetylase HDAC1 and histone demethylase LSD1 held together by the scaffold protein CoREST. Here, we analyze the purified LHC with modified peptide and reconstituted semisynthetic mononucleosome substrates. LHC demethylase activity toward methyl-Lys4 in histone H3 is strongly inhibited by H3 Lys14 acetylation, and this appears to be an intrinsic property of the LSD1 subunit. Moreover, the deacetylase selectivity of LHC unexpectedly shows a marked preference for H3 acetyl-Lys9 versus acetyl-Lys14 in nucleosome substrates but this selectivity is lost with isolated acetyl-Lys H3 protein. This diminished activity of LHC to Lys-14 deacetylation in nucleosomes is not merely due to steric accessibility based on the pattern of sensitivity of the LHC enzymatic complex to hydroxamic acid-mediated inhibition. Overall, these studies have revealed how a single Lys modification can confer a composite of resistance in chromatin to a key epigenetic enzyme complex involved in gene silencing. ; We would like to thank Dirk Schwarzer (Tübingen) for helpful ideas and sharing the F-40 sortase and the globular histone H3 DNA constructs, Cynthia Wolberger (Johns Hopkins) for the core histone DNA constructs, Song Tan (Penn State) for the 146 bp 601 DNA construct, Robert Levendosky and Greg Bowman (Johns Hopkins) for ...