更新于：2024-11-01

EHMT2 x DNMT1

更新于：2024-11-01

基本信息

关联

项与 EHMT2 x DNMT1 相关的药物

CM-272

靶点

DNMT1 x EHMT2

作用机制

DNMT1抑制剂 [+1]

在研机构

University of Navarra [+1]

原研机构

University of Navarra

在研适应症

胆管癌 [+3]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 EHMT2 x DNMT1 相关的临床结果

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100 项与 EHMT2 x DNMT1 相关的转化医学

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0 项与 EHMT2 x DNMT1 相关的专利（医药）

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项与 EHMT2 x DNMT1 相关的文献（医药）

2023-09-01·Biochimica et biophysica acta. General subjects

G9a and DNMT1 inhibition modulates CDKN1A promoter methylation and the cell cycle leading to improvement in kidney fibrosis.

Article

作者: Yang, Yuanyuan ; Zhou, Zijian ; Wu, Zhong ; Gao, Peng ; Wang, Lujia

BACKGROUNDEpigenetic mechanisms, including histone and DNA methylation, play a key role in kidney fibrosis, but the precise mechanism remains unclear. Concerted action between histone and DNA-methyltransferases like G9a and DNMT1 is a common theme in gene expression regulation. We investigated the role of G9a and DNMT1 in kidney fibrosis pathogenesis and aimed to elucidate key G9a and DNMT1 targets contributing to kidney fibrosis maintenance.METHODSG9a and DNMT1 were detected in human fibrotic kidneys, UUO mouse kidneys, and TGFβ1-induced HK-2 cells. G9a and DNMT1 expression was knocked down by siRNA or inhibited with CM272 in HK-2 and UUO mouse, and transcriptomic responses to CM272 were examined. Antifibrogenic activity and safety of CM272 were studied in UUO mouse. Cell cycle were analyzed with flow cytometry. Gene expression regulation was analyzed by chromatin immunoprecipitation and methylation-specific PCR.RESULTSG9a and DNMT1 were overexpressed in human fibrotic kidneys, UUO mouse kidneys, and TGFβ1-induced HK-2 cells. G9a/DNMT1 inhibition potently alleviated fibrosis in vitro and vivo. G9a/DNMT1 inhibition reduced the expression of E2F targets and altered the methylation status of CDKN1A leading to the attenuated cell-cycle arrest. TGFβ1-induced overexpression of G9a or DNMT1 resulted in the enrichment of H3K9me2 and 5-methylcytosine at CDKN1A promoter.CONCLUSIONSOur data link G9a and DNMT1 to CDKN1A regulatory function and kidney fibrosis. Combined targeting G9a and DNMT1 could be a promising strategy for the treatment of kidney fibrosis.

2023-07-12·International journal of molecular sciences

The Novel Role of Zfp296 in Mammalian Embryonic Genome Activation as an H3K9me3 Modulator.

Article

作者: Zheng, Xiaoman ; Liu, Xu ; Zhang, Qian ; Wang, Guoyan ; Zhang, Yong ; Deng, Yi ; Wang, Fan ; Gao, Lu ; Zhang, Zihan

The changes in epigenetic modifications during early embryonic development significantly impact mammalian embryonic genome activation (EGA) and are species-conserved to some degree. Here, we reanalyzed the published RNA-Seq of human, mouse, and goat early embryos and found that Zfp296 (zinc finger protein 296) expression was higher at the EGA stage than at the oocyte stage in all three species (adjusted p-value < 0.05 |log2(foldchange)| ≥ 1). Subsequently, we found that Zfp296 was conserved across human, mouse, goat, sheep, pig, and bovine embryos. In addition, we identified that ZFP296 interacts with the epigenetic regulators KDM5B, SMARCA4, DNMT1, DNMT3B, HP1β, and UHRF1. The Cys₂-His₂(C2H2) zinc finger domain TYPE2 TYPE3 domains of ZFP296 co-regulated the modification level of the trimethylation of lysine 9 on the histone H3 protein subunit (H3K9me3). According to ChIP-seq analysis, ZFP296 was also enriched in Trim28, Suv39h1, Setdb1, Kdm4a, and Ehmt2 in the mESC genome. Then, knockdown of the expression of Zfp296 at the late zygote of the mouse led to the early developmental arrest of the mouse embryos and failure resulting from a decrease in H3K9me3. Together, our results reveal that Zfp296 is an H3K9me3 modulator which is essential to the embryonic genome activation of mouse embryos.

2023-01-01·PloS one

DNA methylation cooperates with H3K9me2 at HCN4 promoter to regulate the differentiation of bone marrow mesenchymal stem cells into pacemaker-like cells.

Article

作者: Sun, XiaoLin ; Jin, Kai ; Ding, Xiangwei ; Ruan, Zhongbao ; Xu, Pei

Sick sinus syndrome (SSS) is a a life-threatening disease, and biological pacemakers derived from bone marrow mesenchymal stem cells (BMSCs) have practical clinical applications. Previous studies demonstrated that epigenetics plays an important role in the differentiation of BMSCs into pacemaker-like cells. However, the underlying mechanisms remain unclear. In the present study, we investigated the role of DNA methylation and histone methylation in pacemaker cells formation and found that changes in DNA and H3K9 methylation occur in the promoter region of the pacemaker cell-specific gene HCN4. In addition, the combined addition of methylation inhibitors was able to improve the efficiency of transduction of Tbx18 in inducing the differentiation of BMSCs into pacemaker-like cells. In vitro experiments have shown that inhibition of DNA methylation and H3K9 methylation can enhance the activity of the HCN4 promoter activity, and both can affect the binding of the transcription factor NKx2.5to the HCN4 promoter region. Further research on the interaction mechanism between DNA methylation and H3K9me2 in the HCN4 promoter region revealed that the two may be coupled, and that the methylesterase G9a and DNMT1 may directly interact to bind as a complex that affects DNA methylation and H3K9me2 regulation of HCN4 transcription. In conclusion, our studies suggest that the mutual coupling of DNA and H3K9 methylation plays a critical role in regulating the differentiation of BMSCs into pacemaker-like cells from the perspective of interactions between epigenetic modifications, and combined methylation is a promising strategy to optimise pacemaker-like cells for in vitro applications.