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

Wang, Jing; Hevi, Sarah; Kurash, Julia K.; Lei, Hong; Bajko, Jeffrey; Su, Hui; Sun, Weidong; Chang, Hua Hua; Xu, Guoliang; Gaudet, François; Li, En; Chen, Taiping

doi:10.1038/ng.268

Cited by 725 publications

(683 citation statements)

References 24 publications

Supporting

Mentioning

644

Contrasting

Unclassified

Order By: Relevance

“…An alternative mechanism could be that LSD1 can directly demethylate the lysine residues of a maintenance DNMT1 and stabilize it from protein degrading. 20 Interestingly, DNMT1 is frequently upregulated in many types of cancer. Whether LSD1, which is often upregulated in cancer as well, might be partly responsible for overexpression of DNMT1 in cancer remains to be determined.…”

Section: Lsd1/kdm1amentioning

confidence: 99%

Epigenetic regulation of cancer growth by histone demethylases

Lim

Metzger

Schüle

et al. 2010

Intl Journal of Cancer

View full text Add to dashboard Cite

Cancer is traditionally viewed as a primarily genetic disorder. However, it is now increasingly apparent that epigenetic abnormalities play a fundamental role in cancer development. Aberrant expression of histone-modifying enzymes has been implicated in the course of tumor initiation and progression. The discovery of a large number of histone demethylases suggests an important role for dynamic regulation of histone methylation in biological processes. The observation that overexpression, amplification or mutations of several histone demethylases have been found in many types of tumors, raise the possibility of using these enzymes as diagnostic tools as well as pave a way for the discovery of novel therapeutic targets and treatment modalities. Here, we review the current knowledge of the potential role of H3K4, H3K9 and H3K27 histone demethylases in tumorigenesis.Recently, it has become apparent that not only genetic mutations but also epigenetic alterations lead to the activation of oncogenes and the loss of function of tumor-suppressor genes. Since epigenetic abnormalities in DNA methylation patterns as well as histone modifications are potentially reversible in contrast to gene mutations, much effort has been directed toward understanding the mechanism of epigenetic aberration to develop epigenetic therapies. Indeed, inhibitors of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) have been approved for treatment of certain types of cancers. Recently, overexpression, amplification or mutations of several histone demethylases have been linked to many types of tumor, raising the possibility of using these enzymes as diagnostic tools and therapeutic targets. Here, we focus mainly on the potential role of some selected histone lysine demethylases in tumorigenesis.The N-terminal tails of histones are subjected to several types of post-translational modifications, including acetylation, methylation, phosphorylation and ubiquitination. The combination of these modifications determines chromatin structure and transcriptional activation or repression of genes. In contrast to other histone modifications, the importance of histone methylations is highlighted because of their enormously specific dynamics with respect to gene regulation. Histone lysine residues on histone H3 and H4 (H3K4, H3K9, H3K27, H3K36, H3K79 and H4K20) can become mono-, dior trimethylated. These modifications are regulated by two classes of enzymes with opposing activities: histone methyltransferases and histone lysine demethylases. LSD1, also known as AOF2 and KDM1, is the first discovered histone lysine demethylase that belongs to the flavin adenine dinucleotide-dependent enzyme family. 1 Subsequently, another family of histone lysine demethylases structurally different from LSD1 was described, all of which sharing the conserved jumonji C (JmjC) domain (Table 1). H3K4 Demethylases in Cancer LSD1/KDM1ATri-and dimethylated H3K4 (H3K4me3/2) are often found at actively transcribed genes. Although H3K4me3 is highly enriched around transcrip...

show abstract

Section: Lsd1/kdm1amentioning

confidence: 99%

Epigenetic regulation of cancer growth by histone demethylases

Lim

Metzger

Schüle

et al. 2010

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…While di-and trimethylated H3K4 (H3K4me3/2) are so-called 'active chromatin marks' associated with active transcription, di-and trimethylated H3K9 (H3K9me3/2) are denoted transcriptionally 'repressive marks' 9 . We and others have shown that lysine-specific demethylase 1 (Lsd1; also known as Kdm1a, Aof2) selectively removes monoand dimethyl groups from H3K4 or H3K9, thereby causing either repression or activation of gene transcription [13][14][15][16][17][18][19] .…”

mentioning

confidence: 99%

Lysine-specific demethylase 1 regulates differentiation onset and migration of trophoblast stem cells

et al. 2014

View full text Add to dashboard Cite

Propagation and differentiation of stem cell populations are tightly regulated to provide sufficient cell numbers for tissue formation while maintaining the stem cell pool. Embryonic parts of the mammalian placenta are generated from differentiating trophoblast stem cells (TSCs) invading the maternal decidua. Here we demonstrate that lysine-specific demethylase 1 (Lsd1) regulates differentiation onset of TSCs. Deletion of Lsd1 in mice results in the reduction of TSC number, diminished formation of trophectoderm tissues and early embryonic lethality. Lsd1-deficient TSCs display features of differentiation initiation, including alterations of cell morphology, and increased migration and invasion. We show that increased TSC motility is mediated by the premature expression of the transcription factor Ovol2 that is directly repressed by Lsd1 in undifferentiated cells. In summary, our data demonstrate that the epigenetic modifier Lsd1 functions as a gatekeeper for the differentiation onset of TSCs, whereby differentiation-associated cell migration is controlled by the transcription factor Ovol2.

show abstract

“…Examples include the biotin-dependent assembly of gene repression complexes (Kuroishi et al 2011), the pantothenic acid-dependent generation of acetyl-CoA (Garrett and Grisham 1995) as a substrate for acetylation of histones, the curcumin-dependent inhibition of histone acetyl transferases (Morimoto et al 2008), the niacin-dependent deacetylation of histones by class III histone deacetylases (HDACs) (Boily et al 2008;Dokmanovic et al 2007), the butyrate-and sulforaphane-dependent inhibition of HDACs (Cummings et al 2001;Davie 2003;Ho et al 2009;Myzak et al 2006), the iron-, riboflavin-, and calcium-dependent demethylation of histones (Tsukada et al 2006;Wang et al 2004Wang et al , 2009, and the niacin-dependent poly(ADP phosphorylation) of histones Kim et al 2005;Messner et al 2010). Nutrient-dependent modification of the epigenome is an exciting field of research, because diet is the one environmental factor that the entire population is exposed to on a daily basis during all stages of life, and where exposure can be modified by lifestyle choices.…”

Section: Discussionmentioning

confidence: 99%

Nutrition, Histone Epigenetic Marks, and Disease

Zempleni

Liu

Xue

2013

Environmental Epigenomics in Health and Disease

View full text Add to dashboard Cite

The dietary intake of essential nutrients and bioactive food compounds is a process that occurs on a daily basis for the entire life span. Therefore, your diet has a great potential to cause changes in the epigenome. Known histone modifications include acetylation, methylation, biotinylation, poly(ADP-ribosylation), ubiquitination, and sumoylation. Some of these modifications depend directly on dietary nutrients. For other modifications, bioactive dietary compounds may alter the activities of enzymes that establish or remove histone marks, thereby altering the epigenome. This chapter provides an overview of diet-dependent epigenomic marks in histones and their links with human health.

show abstract

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

Cited by 725 publications

References 24 publications

Epigenetic regulation of cancer growth by histone demethylases

Epigenetic regulation of cancer growth by histone demethylases

Lysine-specific demethylase 1 regulates differentiation onset and migration of trophoblast stem cells

Nutrition, Histone Epigenetic Marks, and Disease

Contact Info

Product

Resources

About