Last update 01 Nov 2024

EHMT2 x H3K9me3

Last update 01 Nov 2024

Basic Info

Related Targets

EHMT2H3K9me3

Drugs associated with EHMT2 x H3K9me3

MS8511

Target

EHMT2 x H3K9me3

Mechanism

EHMT2 inhibitors [+1]

Active Org.

Icahn School of Medicine at Mount Sinai

Originator Org.

Icahn School of Medicine at Mount Sinai

Active Indication-

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with EHMT2 x H3K9me3

100 Translational Medicine associated with EHMT2 x H3K9me3

0 Patents (Medical) associated with EHMT2 x H3K9me3

Literatures (Medical) associated with EHMT2 x H3K9me3

15 Jul 2024·The FASEB Journal

The G9a histone methyltransferase represses osteoclastogenesis and bone resorption by regulating NFATc1 function

Article

Author: Yamashita, Teruhito ; Nakashima, Kazuhisa ; Nifuji, Akira ; Udagawa, Nobuyuki ; Tachibana, Makoto ; Kimura, Hiroshi ; Komatsu, Koichiro ; Kobayashi, Yasuhiro ; Ideno, Hisashi

AbstractEpigenetic modifications affect cell differentiation via transcriptional regulation. G9a/EHMT2 is an important epigenetic modifier that catalyzes the methylation of histone 3 lysine 9 (H3K9) and interacts with various nuclear proteins. In this study, we investigated the role of G9a in osteoclast differentiation. When we deleted G9a by infection of Cre‐expressing adenovirus into bone marrow macrophages (BMMs) from G9afl/fl(Ehmt2fl/fl) and induced osteoclastic differentiation by the addition of macrophage colony‐stimulating factor (M‐CSF) and receptor activator of NF‐κB ligand (RANKL), the number of TRAP‐positive multinucleated osteoclasts significantly increased compared with control. Furthermore, the mRNA expression of osteoclast markers, TRAP, and cathepsin K, and to a lesser extent, NFATc1, a critical transcription factor, increased in G9a KO cells. Infection of wild‐type (WT) G9a‐expressing adenovirus in G9a KO cells restored the number of TRAP‐positive multinucleated cells. In G9a KO cells, increased nuclear accumulation of NFATc1 protein and decreased H3K9me2 accumulation were observed. Furthermore, ChIP experiments revealed that NFATc1 binding to its target, Ctsk promoter, was enhanced by G9a deletion. For in vivo experiments, we created G9a conditional knock‐out (cKO) mice by crossing G9afl/fl mice with RankCre/+ (Tnfrsf11aCre/+) mice, in which G9a is deleted in osteoclast lineage cells. The trabecular bone volume was significantly reduced in female G9a cKO mice. The serum concentration of the C‐terminal telopeptide of type I collagen (CTX), a bone‐resorbing indicator, was higher in G9a cKO mice. In addition, osteoclasts differentiated from G9a cKO BMMs exhibited greater bone‐resorbing activity. Our findings suggest that G9a plays a repressive role in osteoclastogenesis by modulating NFATc1 function.

01 Jun 2024·Stem Cell Reports

Reduction of H3K9 methylation by G9a inhibitors improves the development of mouse SCNT embryos

Article

Author: Shikata, Daiki ; Ito, Akihiro ; Matoba, Shogo ; Hirose, Michiko ; Tatebe, Takaki ; Watanabe, Naomi ; Hasegawa, Ayumi ; Yoshida, Minoru ; Nakata, Akiko ; Shirai, Fumiyuki ; Ogura, Atsuo

Removal of somatic histone H3 lysine 9 trimethylation (H3K9me3) from the embryonic genome can improve the efficiency of mammalian cloning using somatic cell nuclear transfer (SCNT). However, this strategy involves the injection of histone demethylase mRNA into embryos, which is limiting because of its invasive and labor-consuming nature. Here, we report that treatment with an inhibitor of G9a (G9ai), the major histone methyltransferase that introduces H3K9me1/2 in mammals, greatly improved the development of mouse SCNT embryos. Intriguingly, G9ai caused an immediate reduction of H3K9me1/2, a secondary loss of H3K9me3 in SCNT embryos, and increased the birth rate of cloned pups about 5-fold (up to 3.9%). G9ai combined with the histone deacetylase inhibitor trichostatin A further improved this rate to 14.5%. Mechanistically, G9ai and TSA synergistically enhanced H3K9me3 demethylation and boosted zygotic genome activation. Thus, we established an easy, highly effective SCNT protocol that would enhance future cloning research and applications.

01 Apr 2023·Nature structural & molecular biology

Loss of H3K9 trimethylation alters chromosome compaction and transcription factor retention during mitosis.

Article

Author: Brown, Karen ; Jenuwein, Thomas ; Kramer, Holger ; Wang, Yi-Fang ; Whilding, Chad ; Djeghloul, Dounia ; Veland, Nicolas ; Montavon, Thomas ; Merkenschlager, Matthias ; Futschik, Matthias E. ; Montoya, Alex ; Dimond, Andrew ; Patel, Bhavik ; Fisher, Amanda G. ; Cheriyamkunnel, Sherry

Recent studies have shown that repressive chromatin machinery, including DNA methyltransferases and polycomb repressor complexes, binds to chromosomes throughout mitosis and their depletion results in increased chromosome size. In the present study, we show that enzymes that catalyze H3K9 methylation, such as Suv39h1, Suv39h2, G9a and Glp, are also retained on mitotic chromosomes. Surprisingly, however, mutants lacking histone 3 lysine 9 trimethylation (H3K9me3) have unusually small and compact mitotic chromosomes associated with increased histone H3 phospho Ser10 (H3S10ph) and H3K27me3 levels. Chromosome size and centromere compaction in these mutants were rescued by providing exogenous first protein lysine methyltransferase Suv39h1 or inhibiting Ezh2 activity. Quantitative proteomic comparisons of native mitotic chromosomes isolated from wild-type versus Suv39h1/Suv39h2 double-null mouse embryonic stem cells revealed that H3K9me3 was essential for the efficient retention of bookmarking factors such as Esrrb. These results highlight an unexpected role for repressive heterochromatin domains in preserving transcription factor binding through mitosis and underscore the importance of H3K9me3 for sustaining chromosome architecture and epigenetic memory during cell division.

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