title: A novel mammalian flavin-dependent histone demethylase.
abstract: Methylation of Lys residues on histone proteins is a well known and extensively characterized epigenetic mark. The recent discovery of lysine-specific demethylase 1 (LSD1) demonstrated that lysine methylation can be dynamically controlled. Among the histone demethylases so far identified, LSD1 has the unique feature of functioning through a flavin-dependent amine oxidation reaction. Data base analysis reveals that mammalian genomes contain a gene (AOF1, for amine-oxidase flavin-containing domain 1) that is homologous to the LSD1-coding gene. Here, we demonstrate that the protein encoded by AOF1 represents a second mammalian flavin-dependent histone demethylase, named LSD2. The new demethylase is strictly specific for mono- and dimethylated Lys4 of histone H3, recognizes a long stretch of the H3 N-terminal tail, senses the presence of additional epigenetic marks on the histone substrate, and is covalently inhibited by tranylcypromine. As opposed to LSD1, LSD2 does not form a biochemically stable complex with the C-terminal domain of the corepressor protein CoREST. Furthermore, LSD2 contains a CW-type zinc finger motif with potential zinc-binding sites that are not present in LSD1. We conclude that mammalian LSD2 represents a new flavin-dependent H3-Lys4 demethylase that features substrate specificity properties highly similar to those of LSD1 but is very likely to be part of chromatin-remodeling complexes that are distinct from those involving LSD1.
authors.affiliation: Dipartimento di Genetica e Microbiologia, Università di Pavia, Via Ferrata 1, 27100 Pavia, Italy.
authors.forename: Aristotele
authors.initials: A
authors.lastname: Karytinos
authors.forename: Federico
authors.initials: F
authors.lastname: Forneris
authors.forename: Antonella
authors.initials: A
authors.lastname: Profumo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ciossani
authors.forename: Elena
authors.initials: E
authors.lastname: Battaglioli
authors.forename: Claudia
authors.initials: C
authors.lastname: Binda
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattevi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D003001:Cloning, Molecular; D044127:Epigenesis, Genetic; D005415:Flavins / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008239:Lysine / Q000737:chemistry; D008745:Methylation; D051379:Mice; D008969:Molecular Sequence Data; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D015032:Zinc / Q000032:analysis
chemical_list: D002843:Chromatin; D005415:Flavins; D006657:Histones; D010089:Oxidoreductases, N-Demethylating; D015032:Zinc; D008239:Lysine