Abstract
SummaryThe 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.
Highlights
The molecular machinery that installs and removes post-translational modifications of chromatin has been the subject of increasing research interest not least because these protein complexes are key regulators of gene expression, but they are promising drug targets for the epigenetic treatment of cancer and other diseases (Delcuve et al, 2012; Hesham et al., 2018; Millard et al, 2017; Rowe et al, 2019)
RCOR1, LSD1, and HDAC1 Form a Stable, Enzymatically Active, Stoichiometric Ternary Complex Studies of the CoREST complex to date have investigated the independent activities of the demethylase and deacetylase enzymes
We have observed that corepressor complexes containing class I HDACs (SMRT/NCoR, NuRD, and MiDAC) assemble into either dimeric or tetrameric complexes (Itoh et al, 2015; Millard et al, 2013; Oberoi et al, 2011)
Summary
The molecular machinery that installs and removes post-translational modifications of chromatin has been the subject of increasing research interest not least because these protein complexes are key regulators of gene expression, but they are promising drug targets for the epigenetic treatment of cancer and other diseases (Delcuve et al, 2012; Hesham et al., 2018; Millard et al, 2017; Rowe et al, 2019). The core of the CoREST complex contains two histone modification enzymes, including histone deacetylase 1 or 2 (Humphrey et al, 2001; You et al, 2001), lysine specific demethylase LSD1 (Lee et al, 2005; Shi et al, 2004, 2005), and RCOR1, 2, or 3 that links the two enzymes. The classic enzymatic target for the CoREST complex is the histone H3 tail in which K4 is mono- or di-methylated and K9 is acetylated Removal of these activating marks results in transcriptional repression (Andres et al, 1999; Lakowski et al, 2006; Lee et al, 2005; You et al, 2001)
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