A tail-based mechanism drives nucleosome demethylation by the LSD2/NPAC multimeric complex

• Main Authors: Marabelli, Chiara, Marrocco, Biagina, Pilotto, Simona, Chittori, Sagar, Picaud, Sarah, Marchese, Sara, Ciossani, Giuseppe, Forneris, Federico, Filippakopoulos, Panagis, Schoehn, Guy, Rhodes, Daniela, Subramaniam, Sriram, Mattevi, Andrea
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2019
• Subjects: Histone Demethylation; Cryoelectron Microscopy; DRNTU::Science::Biological sciences
• Online Access: https://hdl.handle.net/10356/93135; http://hdl.handle.net/10220/48524
• Institution: Nanyang Technological University

LSD1 and LSD2 are homologous histone demethylases with opposite biological outcomes related to chromatin silencing and transcription elongation, respectively. Unlike LSD1, LSD2 nucleosome-demethylase activity relies on a specific linker peptide from the multidomain protein NPAC. We used single-particle cryoelectron microscopy (cryo-EM), in combination with kinetic and mutational analysis, to analyze the mechanisms underlying the function of the human LSD2/NPAC-linker/nucleosome complex. Weak interactions between LSD2 and DNA enable multiple binding modes for the association of the demethylase to the nucleosome. The demethylase thereby captures mono- and dimethyl Lys4 of the H3 tail to afford histone demethylation. Our studies also establish that the dehydrogenase domain of NPAC serves as a catalytically inert oligomerization module. While LSD1/CoREST forms a nucleosome docking platform at silenced gene promoters, LSD2/NPAC is a multifunctional enzyme complex with flexible linkers, tailored for rapid chromatin modification, in conjunction with the advance of the RNA polymerase on actively transcribed genes.