Unravelling HDAC Selectivity for Erasing Acetyl Mark on Lys‐5 of Histone H2B

Author:

Shukla Shagun1ORCID,Murmu Sumit12,Mora Tulasiram2,Dhanasekaran Karthigeyan2,Roy Rajendra P.12ORCID

Affiliation:

1. National Institute of Immunology Delhi 110067 India

2. Regional Centre for Biotechnology Faridabad 121001 Haryana India

Abstract

AbstractThe reversible acetylation of specific Lysine residues of histones plays crucial role in the epigenetic regulation of chromatin activity. Importantly, perturbations of acetylation‐deacetylation dynamics have important implications for cancer and neurological disorders. There are 18 human HDACs including sirtuins. The site‐selective acetyl eraser specificity of HDACs is poorly defined. Deciphering the site specificity preference of HDACs from a gamut of lysine in histones may be critical for targeted inhibitor development and delineation of regulatory mechanisms associated with chromatin. Here, we have interrogated the propensity of HDACs to erase acetyl mark at Lys‐5 of H2B namely, H2BK5Ac engineered by a peptide ligation reaction catalyzed by transpeptidase sortase. HDACs and Sirtuins were individually over‐expressed in HEK293 cells and the deacetylation propensity of respective cell lysates was evaluated against H2BK5Ac for initial screening of potential acetyl erasers. This screen indicated HDAC1 as the prime eraser of acetyl mark in H2BK5Ac. The propensity of HDAC1 to erase acetyl mark of H2BK5Ac was further probed using semisynthetic designer nucleosomes with whole cell lysates, recombinant enzyme, and specific inhibitors. Consistent with the above data, siRNA knockdown of HDAC1 and closely related HDAC3 in HEK293 cells prevented the loss of H2BK5 acetylation.

Publisher

Wiley

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