Direct Binding of CoREST1 to SUMO-2/3 Contributes to Gene-Specific Repression by the LSD1/CoREST1/HDAC Complex

Abstract

Post-translational modification of transcription factors by the small ubiquitin related modifier SUMO is associated with transcriptional repression, but the underlying mechanisms remain incompletely described. We have identified binding of the LSD1/CoREST1/HDAC co-repressor complex to SUMO-2. Here we show that CoREST1 binds directly and non-covalently to SUMO-2, but not SUMO-1, and CoREST1 bridges binding of the histone demethylase LSD1 to SUMO-2. Depletion of SUMO-2/3 conjugates led to transcriptional de-repression, reduced occupancy of CoREST1 and LSD1 and changes in histone methylation and acetylation at some, but not all, LSD1/CoREST1/HDAC target genes. We have identified a non-consensus SUMO-interaction motif (SIM) in CoREST1 required for SUMO-2 binding and we show that mutation of the CoREST1 SIM disrupted SUMO-2 binding and transcriptional repression of some neuronal specific genes in non-neuronal cells. Our results reveal that direct interactions between CoREST1 and SUMO-2 mediate SUMO-dependent changes in chromatin structure and transcription important for cell type-specific gene expression.

The SUMO E3 Ligase-Like Proteins PIAL1 and PIAL2 Interact with MOM1 and Form a Novel Complex Required for Transcriptional Silencing

“…In yeast and animals, SUMO modification is involved in various biological processes including chromatin organization and transcriptional regulation (Shin et al, 2005;Shiio and Eisenman, 2003;Nathan et al, 2006;Cubeñas-Potts and Matunis, 2013). Noncovalent interaction of SUMO proteins with chromatin-associated proteins is also required for SUMO-dependent transcriptional regulation (Stielow et al, 2008;Ouyang et al, 2009;Cubeñas-Potts and Matunis, 2013). In Arabidopsis, mass spectrometric analysis of purified sumoylated proteins demonstrated that many SUMO substrates are involved in chromatin structure regulation, transcription, and RNA metabolism (Budhiraja et al, 2009;Miller et al, 2010).…”

Poly-Small Ubiquitin-like Modifier (PolySUMO)-binding Proteins Identified through a String Search

“…Like ubiquitylation, sumoylation modifies many proteins in diverse cellular processes yet has distinct functional consequences (1,2). Sumoylation promotes a protein-protein interaction through the physical contact between SUMO and the SUMO-interacting motif (SIM), a ␤-strand consisting of hydrophobic (in the pattern of (V/I/L)(V/I/L)X(V/I/L), (V/I/ L)X(V/I/L)(V/I/L), or (V/I/L)X(V/I/L)X(V/I/L)) and acidic residues (3)(4)(5)(6)(7). As all SIMs are believed to dock onto the same site on SUMO, they constitute a single class of SUMO binding motif.…”

Transcriptional Repression by Sumoylation of Epstein-Barr Virus BZLF1 Protein Correlates with Association of Histone Deacetylase

“…Therefore, we speculate that there must be much more active and powerful repres- sion mechanism rather than just inhibition of the interaction with CBP. Recently, it has been reported that sumoylation of cellular transcription factors promotes interaction with repressor complexes including HDAC (42)(43)(44)(45)(46)(47)(48). We, therefore, tested the interaction between SUMO-modified BZLF1 and HDAC and showed that at least HDAC3 associates with the sumoylated form of BZLF1 but not clearly with the unsumoylated form, suggesting that SUMO-mediated acetylation levels of chromatin affect the BZLF1-dependent transcription.…”