New roles of flavoproteins in molecular cell biology: Histone demethylase LSD1 and chromatin

Abstract

Lysine‐specific demethylase 1 (LSD1) is an enzyme that removes methyl groups from mono‐ and dimethylated Lys4 of histone H3, a post‐translational modification associated with gene activation. Human LSD1 was the first histone demethylase to be discovered and this enzymatic activity is conserved among eukaryotes. LSD1 has been identified in a number of chromatin‐remodeling complexes that control gene transcription and its demethylase activity has also been linked to pathological processes including tumorigenesis. The 852‐residue sequence of LSD1 comprises an amine oxidase domain which identifies a family of enzymes that catalyze the FAD‐dependent oxidation of amine substrates ranging from amino acids to aromatic neurotransmitters. Among these proteins, LSD1 is peculiar in that it acts on a protein substrate in the nuclear environment of chromatin‐remodeling complexes. This functional divergence occurred during evolution from the eubacteria to eukaryotes by acquisition of additional domains such as the SWIRM domain. The N‐terminal part of LSD1, predicted to be disordered, contains linear motifs that might represent functional sites responsible for the association of this enzyme with a variety of transcriptional protein complexes. LSD1 shares structural features with other flavin amine oxidases, including the overall fold of the amine oxidase domain region and details in the active site that are relevant for amine substrate oxidation.

The endoglycosidase heparanase enters the nucleus of T lymphocytes and modulates H3 methylation at actively transcribed genes via the interplay with key chromatin modifying enzymes

“…Previous studies have shown that LSD1 cannot erase H3K4 and H3K9 methylation marks simultaneously on histone peptides. 65,66 Our findings in vivo for the first time suggest that the heparanase/LSD1 complex can simultaneously mediate H3K4 and H3K9 methylation marks on activated genes. It is plausible that the tethering of heparanase to LSD1 may induce conformational changes to facilitate the binding of LSD1 and demethylation of both H3K4 and H3K9 residues.…”

DNA oxidation drives Myc mediated transcription

“…10 The enzyme responsible for demethylation of H3K4 is LSD1. LSD1 is a multidomain protein described to have a role in activated and repressed gene expression programs; 11,12 it was originally identified as part of the multiprotein repressor complex CoREST. Repression of REST target genes has been explained, at least in part, through the recruitment of the LSD1-CoREST-HDAC core followed by histone deacetylation on H3 and H4 and demethylation of H3K4.…”

The Redox Basis of Epigenetic Modifications: From Mechanisms to Functional Consequences

“…4B). LSD1 belongs to the family of flavin adenine dinucleotide (FAD)-dependent amine oxidases (78). In the rate-limiting step, LSD1 catalyzes the 2-electron oxidation of the C-N methylamine bond concomitant with the 2-electron reduction of the FAD cofactor.…”