Interplay among nucleosomal DNA, histone tails, and corepressor CoREST underlies LSD1-mediated H3 demethylation

With its noncatalytic domains, DNA-binding regions, and a catalyticcore targeting the histone tails, LSD1-CoREST (lysine-specific demeth-ylase 1; REST corepressor) is an ideal model system to study theinterplay between DNA binding and histone modification in nucle-osome recognition. To this end, we covalently associated LSD1-CoREST to semisynthetic nucleosomal particles. This enabled bio-chemical and biophysical characterizations of nucleosome bindingand structural elucidation by small-angle X-ray scattering, whichwas extensively validated through binding assays and site-directedmutagenesis of functional interfaces. Our results suggest that LSD1-CoREST functions as an ergonomic clamp that induces the detach-ment of the H3 histone tail from the nucleosomal DNA to make itavailable for capture by the enzyme active site. The key notionemerging from these studies is the inherently competitive natureof the binding interactions because nucleosome tails, chromatinmodifiers, transcription factors, and DNA represent sites for mul-tiple and often mutually exclusive interactions.