Mechanism of crosstalk between the LSD1 demethylase and HDAC1 deacetylase in the CoREST complex

Song, Y. et al. (2020) Mechanism of crosstalk between the LSD1 demethylase and HDAC1 deacetylase in the CoREST complex. Cell Reports, 30(8), 2699-2711.e8. (doi: 10.1016/j.celrep.2020.01.091) (PMID:32101746)

Abstract

The transcriptional corepressor complex CoREST is one of seven histone deacetylase complexes that regulate the genome through controlling chromatin acetylation. The CoREST complex is unique in containing both histone demethylase and deacetylase enzymes, LSD1 and HDAC1, held together by the RCOR1 scaffold protein. To date, it has been assumed that the enzymes function independently within the complex. Now, we report the assembly of the ternary complex. Using both structural and functional studies, we show that the activity of the two enzymes is closely coupled and that the complex can exist in at least two distinct states with different kinetics. Electron microscopy of the complex reveals a bi-lobed structure with LSD1 and HDAC1 enzymes at opposite ends of the complex. The structure of CoREST in complex with a nucleosome reveals a mode of chromatin engagement that contrasts with previous models.

• Item Type: Articles
• Additional Information: We are grateful to the PROTEX facility (University of Leicester) for preparation of expression clones; the staff at B21 at the Diamond Light Source for the SAXS data collection; Ian Hands-Portman at the Warwick Life Sciences Imaging Suite (now Advanced Bioimaging Research Technology Platform), University of Warwick, using equipment funded by the Wellcome Trust (055663/Z/98/Z); and the eBIC facility at the Diamond Light Source for initial cryo-EM datasets; and the MRC Toxicology Electron Microscopy facility. We acknowledge the Midlands Regional CryoEM Facility at the Leicester Institute of Structural and Chemical Biology (LISCB) and major funding from MRC (MC_PC_17136). J.W.R.S. is a Wellcome Trust Senior Investigator (100237/Z/12/Z) and Royal Society Wolfson Research Merit Award Holder. D.F.H. was supported by the Wellcome Trust (101569/Z/13/Z) and Leverhulme Trust (RPG-2016-268). P.A.C. was supported by the NIH (GM62437).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jamieson, Professor Andrew
• Authors: Song, Y., Dagil, L., Fairall, L., Robertson, N., Wu, M., Ragan, T.J., Savva, C. G., Saleh, A., Morone, N., Kunze, M. B.A., Jamieson, A. G., Cole, P. A., Hansen, D. F., and Schwabe, J. W.R.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: Cell Reports
• Publisher: Elsevier
• ISSN: 2211-1247
• ISSN (Online): 2211-1247
• Published Online: 25 February 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Cell Reports 30(8):2699-2711.e8
• Publisher Policy: Reproduced under a Creative Commons License