| Autor: |
Kelly RDW; Department of Molecular and Cell biology, Henry Wellcome Building, University of Leicester, Leicester, LE1 7RH, UK., Chandru A; Department of Molecular and Cell biology, Henry Wellcome Building, University of Leicester, Leicester, LE1 7RH, UK., Watson PJ; Institute of Structural and Chemical biology, Henry Wellcome Building, Department of Molecular and Cell biology, University of Leicester, Leicester, LE1 7RH, UK., Song Y; Institute of Structural and Chemical biology, Henry Wellcome Building, Department of Molecular and Cell biology, University of Leicester, Leicester, LE1 7RH, UK., Blades M; Bioinformatics and Biostatistics Analysis Support Hub (B/BASH), University of Leicester, Leicester, LE1 7RH, UK., Robertson NS; Department of Chemistry, University of Cambridge, Cambridge, CB2 1GA, UK., Jamieson AG; School of Chemistry, Joseph Black Building, University Avenue, University of Glasgow, Glasgow, G12 8QQ, Scotland., Schwabe JWR; Institute of Structural and Chemical biology, Henry Wellcome Building, Department of Molecular and Cell biology, University of Leicester, Leicester, LE1 7RH, UK., Cowley SM; Department of Molecular and Cell biology, Henry Wellcome Building, University of Leicester, Leicester, LE1 7RH, UK. smc57@le.ac.uk. |
| Abstrakt: |
Proteomic analysis of histones has shown that they are subject to a superabundance of acylations, which extend far beyond acetylation, to include: crotonylation, propionylation, butyrylation, malonylation, succinylation, β-hydroxybutyrylation and 2-hydroxyisobutyrylation. To date, much of the functional data has focussed on histone crotonylation which, similar to acetylation, has been associated with positive gene regulation and is added by the acyltransferase, p300. Although Sirtuins 1-3, along with HDAC3, have been shown to possess decrotonylase activity in vitro, there is relatively little known about the regulation of histone crotonylation in vivo. Here we show that Histone Deacetylase 1 and 2 (HDAC1/2), the catalytic core of numerous co-repressor complexes, are important histone decrotonylase enzymes. A ternary complex of HDAC1/CoREST1/LSD1 is able to hydrolyse both histone H3 Lys18-acetyl (H3K18ac) and H3 Lys18-crotonyl (H3K18cr) peptide substrates. Genetic deletion of HDAC1/2 in ES cells increases global levels of histone crotonylation and causes an 85% reduction in total decrotonylase activity. Furthermore, we mapped H3K18cr in cells using ChIP-seq, with and without HDAC1/2, and observed increased levels of crotonylation, which largely overlaps with H3K18ac in the vicinity of transcriptional start sites. Collectively, our data indicate that HDAC1/2 containing complexes are critical regulators of histone crotonylation in vivo. |
