Multivalent interactions mediate SNAIL transcription factor stimulation of the nucleosome deacetylase activity of the CoREST complex

Abstract

SNAIL is a transcription factor that plays a role in development and cancer. SNAIL contains an N-terminal SNAG domain that is a high-affinity ligand for the histone substrate binding lysine-specific demethylase 1 (LSD1). SNAIL also contains a C-terminal zinc finger domain that binds to DNA E-box sequences. SNAIL and related transcription factor family members are known to recruit LSD1-containing protein complexes to specific sites in chromatin to regulate gene expression. LSD1 can form a multiprotein complex with histone deacetylase 1 (HDAC1) and CoREST scaffolding protein (LHC). In this study, we use a purified system to analyze the role of SNAIL in modulating nucleosome deacetylation by the LHC complex. We find that SNAIL enhances nucleosome deacetylase activity of the LHC complex at multiple histone H3 sites through multivalent interactions. Enhanced nucleosome deacetylation is dependent on SNAIL's SNAG and zinc finger domains. Unexpectedly, we find that SNAIL-stimulated nucleosome deacetylation by LHC also involves interactions of the nucleosome histone acidic patch, including histone H2A acidic residues. Modeling and mutagenesis experiments suggest that this acidic patch could engage a basic patch in the disordered segment of LSD1. Together, these findings reveal how a transcription factor can influence a cascade of molecular recognition events to regulate chromatin structure.