A novel mammalian flavin-dependent histone demethylase

J Biol Chem. 2009 Jun 26;284(26):17775-82. doi: 10.1074/jbc.M109.003087. Epub 2009 Apr 30.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Chromatin / genetics*
  • Chromatin / metabolism
  • Cloning, Molecular
  • Epigenesis, Genetic
  • Flavins / genetics
  • Flavins / metabolism*
  • Histones / metabolism*
  • Hydrogen-Ion Concentration
  • Kinetics
  • Lysine / chemistry
  • Methylation*
  • Mice
  • Molecular Sequence Data
  • Oxidoreductases, N-Demethylating / genetics
  • Oxidoreductases, N-Demethylating / metabolism*
  • Sequence Homology, Amino Acid
  • Substrate Specificity
  • Zinc / analysis

Substances

  • Chromatin
  • Flavins
  • Histones
  • Oxidoreductases, N-Demethylating
  • Zinc
  • Lysine