A Tail-Based Mechanism Drives Nucleosome Demethylation by the LSD2/NPAC Multimeric Complex | Zendy

Chiara Marabelli | Zendy; Biagina Marrocco | Zendy; Simona Pilotto | Zendy; Sagar Chittori | Zendy; S. Picaud | Zendy; Sara Marchese | Zendy; Giuseppe Ciossani | Zendy; Federico Forneris | Zendy; P. Filippakopoulos | Zendy; Guy Schoehn | Zendy; Daniela Rhodes | Zendy; Sriram Subramaniam | Zendy; Andrea Mattevi | Zendy

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A Tail-Based Mechanism Drives Nucleosome Demethylation by the LSD2/NPAC Multimeric Complex

Author(s) -

Chiara Marabelli,

Biagina Marrocco,

Simona Pilotto,

Sagar Chittori,

S. Picaud,

Sara Marchese,

Giuseppe Ciossani,

Federico Forneris,

P. Filippakopoulos,

Guy Schoehn,

Daniela Rhodes,

Sriram Subramaniam,

Andrea Mattevi

Publication year - 2019

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2019.03.061

Subject(s) - nucleosome , linker dna , chromatin , demethylase , histone h3 , histone , biology , microbiology and biotechnology , histone code , chromatosome , histone methylation , transcription (linguistics) , biochemistry , biophysics , dna , chemistry , dna methylation , gene , gene expression , linguistics , philosophy

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.

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