Histone Demethylation Mediated by the Nuclear Amine Oxidase Homolog LSD1

Abstract

Posttranslational modifications of histone N-terminal tails impact chromatin structure and gene transcription. While the extent of histone acetylation is determined by both acetyltransferases and deacetylases, it has been unclear whether histone methylation is also regulated by enzymes with opposing activities. Here, we provide evidence that LSD1 (KIAA0601), a nuclear homolog of amine oxidases, functions as a histone demethylase and transcriptional corepressor. LSD1 specifically demethylates histone H3 lysine 4, which is linked to active transcription. Lysine demethylation occurs via an oxidation reaction that generates formaldehyde. Importantly, RNAi inhibition of LSD1 causes an increase in H3 lysine 4 methylation and concomitant derepression of target genes, suggesting that LSD1 represses transcription via histone demethylation. The results thus identify a histone demethylase conserved from S. pombe to human and reveal dynamic regulation of histone methylation by both histone methylases and demethylases.

Roles of jumonji and jumonji family genes in chromatin regulation and development

“…Shi et al showed that LSD1, a nuclear amine oxidase, found in several histone deacetylase complexes, specifically demethylates mono-or di-methyl-H3-K4 (H3-K4me1 or H3-K4me2, respectively) in a flavin adenine dinucleotide-dependent oxidase reaction (Shi et al, 2004). However, this type of enzyme cannot demethylate tri-methylated residues.…”

CRISPR-based reagents to study the influence of the epigenome on gene expression

“…In contrast, Lsd1 (KDM1A), a flavin‐containing amino oxidase, was the first enzyme identified that had the ability to demethylate mono‐ and dimethylated histone H3 lysine 4 histone substrates 27. Subsequently, a second, larger family of Fe (II) and 2‐oxoglutarate oxygenases, which contain a catalytic domain which has been termed the ‘Jumonji domain’, was identified 28.…”

Structural dynamics of protein lysine methylation and demethylation

“…There are many examples of N(itrogen)-methylations (of arginine, lysine, glutamine, asparagine, histidine residues, and the amino group at the N terminus) in the cell. While it is not certain that all N-methylations are reversible, recent discoveries showed that a human nuclear peptidyl arginine deiminase, PAD4, antagonizes methylation on the arginine residues by converting arginine to citrulline [92][93][94] (Figure 5); a human nuclear amine oxidases, LSD1, functions as a histone di/mono-methyl-lysine demethylase via an oxidation reaction [95][96][97]; and JmjC domain-containing hydroxylase-like proteins are able to demethylate mono-, di-, or tri-methylated lysines [98,99], which was first proposed for S. pombe Epe1 [100].…”

“…LSD1 (also known as BHC110), named after protein lysine-specific-demethylase 1 [95], is found in histone modification complexes that control cell-specific gene expression. Within these complexes, REST (RE1-silencing transcription factor) corepressor CoREST enables LSD1 to demethylate nucleosomes [96,97], while BHC80 (BRAF-HDAC complex) inhibits LSD1 activity [96].…”

“…The figure panels are adopted from [94]. [95]. (b) The solution NMR structure of the SIWRM domain of LSD1.…”