The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation

  title={The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation},
  author={Jing Wang and Sarah Hevi and Julia K. Kurash and Hong Lei and Frédérique Gay and Jeffrey Bajko and Hui Su and Wei-Sheng Sun and Hua Chang and Guoliang Xu and François Gaudet and En Li and Taiping Chen},
  journal={Nature Genetics},
Histone methylation and DNA methylation cooperatively regulate chromatin structure and gene activity. How these two systems coordinate with each other remains unclear. Here we study the biological function of lysine-specific demethylase 1 (LSD1, also known as KDM1 and AOF2), which has been shown to demethylate histone H3 on lysine 4 (H3K4) and lysine 9 (H3K9). We show that LSD1 is required for gastrulation during mouse embryogenesis. Notably, targeted deletion of the gene encoding LSD1 (namely… 

LSD1: more than demethylation of histone lysine residues

The molecular mechanism by which LSD1 displays its dual effect on gene expression (related to the specific lysine target) is analyzed, placing final emphasis on the use of pharmacological inhibitors of its activity in future clinical studies to fight cancer.

Methylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3 and CRL4DCAF5 ubiquitin ligase

It is reported that the methylated lysine 142 of DNMT1, a major DNA methyltransferase that preserves epigenetic inheritance of DNA methylation patterns during DNA replication, is demethylated by LSD1, and a novel methyl-binding protein, L3MBTL3, binds the K142-methylatedDNMT1 and recruits a novel CRL4DCAF5 ubiquitin ligase to degrade DNMT 1.

The interplay between the lysine demethylase KDM1A and DNA methyltransferases in cancer cells is cell cycle dependent

The findings propose a mechanistic link between KDM1A and DNA methyltransferases in cancer cells and suggest that the KDM2A/DNMT1 interaction may play a role during replication, and strengthens the idea that DNMTs can exert functions unrelated to act on DNA methylation.

Silencing Lysine-Specific Histone Demethylase 1 (LSD1) Causes Increased HP1-Positive Chromatin, Stimulation of DNA Repair Processes, and Dysregulation of Proliferation by Chk1 Phosphorylation in Human Endothelial Cells

The knockdown of LSD1 in endothelial cells leads to increased HP1-positive chromatin, the stimulation of DNA repair processes, and the dysregulation of proliferation machinery.

KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints

Differential DNA methylation of the paternal and maternal alleles regulates the parental origin-specific expression of imprinted genes in mammals. The methylation imprints are established in male and

Loss of LSD1 (lysine-specific demethylase 1) suppresses growth and alters gene expression of human colon cancer cells in a p53- and DNMT1(DNA methyltransferase 1)-independent manner

The results of the present study suggested that LSD 1 is critical in the regulation of cell proliferation, but also indicated that LSD1 is not an absolute requirement for the stabilization of either p53 or DNMT1.

Inhibition of histone demethylase, LSD2 (KDM1B), attenuates DNA methylation and increases sensitivity to DNMT inhibitor-induced apoptosis in breast cancer cells

An important role for LSD2 is demonstrated in regulation of DNA methylation and gene silencing in breast cancer, and inhibition of LSD2 in combination with DNA methyltransferase inhibition represents a novel approach for epigenetic therapy of breast cancer.

Demethylation of RB regulator MYPT1 by histone demethylase LSD1 promotes cell cycle progression in cancer cells.

MYPT1 was unstable in murine cells deficient in SETD7, supporting the concept that MYPT1 protein stability is physiologically regulated by methylation status, and revealing the significance of LSD1 overexpression in human carcinogenesis.

SET8 prevents excessive DNA methylation by methylation-mediated degradation of UHRF1 and DNMT1

It is shown that SET8, a cell-cycle-regulated protein methyltransferase, controls protein stability of both UHRF1 and DNMT1 through methylation-mediated, ubiquitin-dependent degradation and consequently prevents excessive DNA methylation.

Recruitment of Dnmt1 roles of the SRA protein Np95 (Uhrf1) and other factors.




p53 is regulated by the lysine demethylase LSD1

Lysine methylation provides similar regulatory complexity for non-histone proteins and for histones and that the methylation status at a single lysine residue confers distinct regulatory output.

Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase

The isolation of KRYPTONITE, a methyltransferase gene specific to H3 Lys 9, identified in a mutant screen for suppressors of gene silencing at the Arabidopsis thaliana SUPERMAN (SUP) locus is reported, which suggests that CpNpG DNA methylation is controlled by histone H 3 Lys 9 methylation, through interaction of CMT3 with methylated chromatin.

In vivo stabilization of the Dnmt1 (cytosine-5)- methyltransferase protein

  • F. DingJ. Chaillet
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 2002
The intrinsic stability of the Dnmt1o protein is the most likely reason for its use as a maternal-effect protein; stable ooplasmic stores of DnMT1o would be available to traffick into the nuclei of the eight-cell stage embryo and maintain methylation patterns on alleles of imprinted genes during the fourth embryonic S phase.

A histone H3 methyltransferase controls DNA methylation in Neurospora crassa

It is demonstrated that recombinant DIM-5 protein specifically methylates histone H3 and that replacement of lysine 9 in hist one H3 with either a leucine or an arginine phenocopies the dim-5 mutation, concluding that DNA methylation depends on histone methylation.

Repression of p53 activity by Smyd2-mediated methylation

A lysine methyltransferase, Smyd2, is reported that methylates a previously unidentified site, Lys 370, in p53, which is repressing to p53-mediated transcriptional regulation and providing regulatory cross-talk between post-translational modifications.

Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication.

Direct cooperation between DNMT1 and G9a provides a mechanism of coordinated DNA and H3K9 methylation during cell division and led to enhanced DNA and histone methylation of in vitro assembled chromatin substrates.