更新于：2024-11-01

DNMT1

更新于：2024-11-01

基本信息

别名

AIM、CXXC-type zinc finger protein 9、CXXC9

+ [10]

简介

Methylates CpG residues. Preferentially methylates hemimethylated DNA. Associates with DNA replication sites in S phase maintaining the methylation pattern in the newly synthesized strand, that is essential for epigenetic inheritance. Associates with chromatin during G2 and M phases to maintain DNA methylation independently of replication. It is responsible for maintaining methylation patterns established in development. DNA methylation is coordinated with methylation of histones. Mediates transcriptional repression by direct binding to HDAC2. In association with DNMT3B and via the recruitment of CTCFL/BORIS, involved in activation of BAG1 gene expression by modulating dimethylation of promoter histone H3 at H3K4 and H3K9. Probably forms a corepressor complex required for activated KRAS-mediated promoter hypermethylation and transcriptional silencing of tumor suppressor genes (TSGs) or other tumor-related genes in colorectal cancer (CRC) cells (PubMed:24623306). Also required to maintain a transcriptionally repressive state of genes in undifferentiated embryonic stem cells (ESCs) (PubMed:24623306). Associates at promoter regions of tumor suppressor genes (TSGs) leading to their gene silencing (PubMed:24623306). Promotes tumor growth (PubMed:24623306).

关联

项与 DNMT1 相关的药物

Decitabine/Cedazuridine

地西他滨/西达尿苷

靶点

CDA x DNMT1

作用机制

CDA抑制剂 [+1]

在研机构

National Cancer Institute [+11]

原研机构

Astex Pharmaceuticals, Inc.

在研适应症

急性髓性白血病 [+21]

非在研适应症

造血干细胞移植 [+3]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2020-07-07

Triclabendazole

三氯苯达唑

靶点

DNMT1

作用机制

DNMT1抑制剂

在研机构

Novartis Pharmaceuticals Corp.

原研机构

Novartis Pharma AG

在研适应症

片形吸虫病

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2019-02-13

Decitabine

地西他滨

靶点

DNMT1

作用机制

DNMT1抑制剂

在研机构

Janssen Pharmaceuticals, Inc. [+10]

原研机构

Eisai Co., Ltd.

在研适应症

难治性贫血 [+21]

非在研适应症

急性红细胞白血病 [+24]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2006-05-02

2,041

项与 DNMT1 相关的临床试验

NCT06514261 / Recruiting临床1期IIT

Phase 1 Trial of Iadademstat in Combination With Venetoclax and Azacitidine in Patients With Treatment Naive AML

This phase I trial tests safety, side effects and best dose of iadademstat with azacitidine and venetoclax for the treatment of patients with acute myeloid leukemia (AML) who have not receive treatment (treatment naive). Chemotherapy drugs, such as iadademstat and azacitidine work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving iadademstat with azacitidine and venetoclax may be safe and tolerable in treating patients with treatment naive AML.

开始日期2025-07-15

申办/合作机构

National Cancer Institute

ACTRN12624000738527 / Not yet recruiting临床2期IIT

AMLM22/D4: The International AML Platform Consortium (IAPC) trial – is a randomised, 2-arm trial that will investigate the efficacy of oral Azacitidine combined with an allogeneic dendritic cell vaccine vididencel, compared with oral Azacitidine alone, in maintaining or inducing negativity for measurable residual disease (MRD) in AML patients in first complete remission (CR1) following intensive chemotherapy.

开始日期2025-06-30

申办/合作机构

The Australian Leukaemia & Lymphoma Group

[+1]

NCT06454409 / Not yet recruiting临床1期IIT

A Phase 1b Study of the Multi-Kinase Inhibitor Regorafenib in Combination With the BCL-2 Inhibitor Venetoclax Plus Azacitidine in Patients With Relapsed/Refractory Acute Myeloid Leukemia

This phase Ib trial tests the safety, side effects, best dose and effectiveness of regorafenib in combination with venetoclax and azacitidine in treating patients with acute myeloid leukemia (AML) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Regorafenib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps to slow or stop the spread of cancer cells. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Azacitidine is in a class of medications called demethylation agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells. Giving regorafenib in combination with venetoclax and azacitidine may be safe, tolerable and/or effective in treating patients with relapsed or refractory AML.

开始日期2025-03-20

申办/合作机构

City of Hope National Medical Center

[+1]

100 项与 DNMT1 相关的临床结果

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100 项与 DNMT1 相关的转化医学

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0 项与 DNMT1 相关的专利（医药）

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5,859

项与 DNMT1 相关的文献（医药）

2024-12-31·Clinical and experimental hypertension (New York, N.Y. : 1993)

Gestational diabetes causes hyperactivity of the sympathetic nervous system and hypertension in adult mice offspring.

Article

作者: Luo, Hao ; Zhu, Jun ; Zhu, Xingyu ; Bai, Xue ; Yang, Li ; Wang, Chunxiang ; Hu, Zegang

BACKGROUNDGestational diabetes can lead to increased blood pressure in offspring, accompanied by impaired renal sodium excretion function and vasoconstriction and diastole dysfunction. However, there are few studies on whether it is accompanied by increased sympathetic nerve activity.METHODSPregnant C57BL/6 mice were intraperitoneally injected with streptozotocin (35 mg/kg) or citrate buffer at day 0 of gestation. The mice of control mother offspring (CMO) and diabetic mother offspring (DMO) at 16 weeks of age were infused with vehicle (artificial cerebrospinal fluid, aCSF, 0.4 μL/h) or tempol (1 mmol/L, 0.4 μL/h) into the bilateral paraventricular nucleus (PVN) of mice for 4 weeks, respectively.RESULTSCompared with CMO group, SBP and peripheral sympathetic nerve activity (increased heart rate, LF/HF and plasma norepinephrine and decreased SDNN and RMSSD) were increased in DMO group, which was accompanied by increased angiotensin II type-1 receptor (AT₁R) expression and function in PVN. The increase in AT₁R expression levels was attributed to a decrease in the methylation level of the AT₁R promoter region, resulting in an increase in AT₁R mRNA levels in PVN of DMO. Moreover, compared with CMO group, the levels of oxidative stress were increased and DNMT1 expression was decreased in PVN of DMO. Bilateral PVN infusion of tempol attenuated oxidative stress increased the level of DNMT1 expression and the binding of DNMT1 to the AT₁R promoter region, which reduced mRNA and protein expression level of AT₁R, heart rate and SBP in DMO, but not in CMO.CONCLUSIONSThe present study provides evidence for overactive sympathetic nervous systems in the pathogenesis of gestational diabetes-induced hypertension in offspring. Central antioxidant intervention in the PVN may be an important treatment strategy for fetal-programmed hypertension.

2024-12-01·Molecular Biology Reports

Expression profile of viability and stress response genes as a result of resveratrol supplementation in vitrified and in vitro produced cattle embryos

Article

作者: Ragab, Refaat S A ; Ibrahim, Sally ; Saber, Yasser H A ; Ahmed, Wahid M ; Mahmoud, Karima Gh M ; Seida, Adel A M

BACKGROUNDResveratrol, a potent antioxidant, is known to induce the up-regulation of the internal antioxidant system. Therefore, it holds promise as a method to mitigate cryopreservation-induced injuries in bovine oocytes and embryos. This study aimed to (i) assess the enhancement in the quality of in vitro produced bovine embryos following resveratrol supplementation and (ii) monitor changes in the expression of genes associated with oxidative stress (GPX4, SOD, CPT2, NFE2L2), mitochondrial function (ATP5ME), endoplasmic reticulum function (ATF6), and embryo quality (OCT4, DNMT1, CASP3, ELOVL5).METHODS AND RESULTSThree groups of in vitro bovine embryos were cultured with varying concentrations of resveratrol (0.01, 0.001, and 0.0001 µM), with a fourth group serving as a control. Following the vitrification process, embryos were categorized as either good or poor quality. Blastocysts were then preserved at - 80 °C for RNA isolation, followed by qRT-PCR analysis of selected genes. The low concentrations of resveratrol (0.001 µM, P < 0.05 and 0.0001 µM, P < 0.01) significantly improved the blastocyst rate compared to the control group. Moreover, the proportion of good quality vitrified embryos increased significantly (P < 0.05) in the groups treated with 0.001 and 0.0001 µM resveratrol compared to the control group. Analysis of gene expression showed a significant increase in OCT4 and DNMT1 transcripts in both good and poor-quality embryos treated with resveratrol compared to untreated embryos. Additionally, CASP3 expression was decreased in treated good embryos compared to control embryos. Furthermore, ELOVL5 and ATF6 transcripts were down-regulated in treated good embryos compared to the control group. Regarding antioxidant-related genes, GPX4, SOD, and CPT2 transcripts increased in the treated embryos, while NFE2L2 mRNA decreased in treated good embryos compared to the control group.CONCLUSIONSResveratrol supplementation at low concentrations effectively mitigated oxidative stress and enhanced the cryotolerance of embryos by modulating the expression of genes involved in oxidative stress response.

2024-12-01·Cellular and Molecular Life Sciences

METTL16 inhibits papillary thyroid cancer tumorigenicity through m6A/YTHDC2/SCD1-regulated lipid metabolism

Article

作者: Duan, Feifan ; Chen, Shuya ; Zhou, Lei ; Gao, Yu ; Zhang, Yukun ; Wang, Wenjing ; Sheng, Zhiyong ; Wang, Yaju ; Li, Qiang ; Meng, Xiangshu

AbstractPapillary thyroid carcinoma (PTC) stands as the leading cancer type among endocrine malignancies, and there exists a strong correlation between thyroid cancer and obesity. However, the clinical significance and molecular mechanism of lipid metabolism in the development of PTC remain unclear. In this study, it was demonstrated that the downregulation of METTL16 enhanced lipid metabolism and promoted the malignant progression of PTC. METTL16 was expressed at lower levels in PTC tissues because of DNMT1-mediated hypermethylation of its promoter. Loss- and gain-of-function studies clarified the effects of METTL16 on PTC progression. METTL16 overexpression increased the abundance of m6A in SCD1 cells, increasing RNA decay via the m6A reader YTHDC2. The SCD1 inhibitor A939572 inhibited growth and slowed down lipid metabolism in PTC cells. These results confirm the crucial role of METTL16 in restraining PTC progression through SCD1-activated lipid metabolism in cooperation with YTHDC2. This suggests that the combination of METTL16 and anti-SCD1 blockade might constitute an effective therapy for PTC.

项与 DNMT1 相关的新闻（医药）

2024-10-16

·生物谷

中国科学院分子细胞科学卓越创新中心徐国良组合作揭示DNA甲基化抑制性别决定区的减数分裂重组

10月9日，国际学术期刊Science Advances在线发表了中国科学院分子细胞科学卓越创新中心（生物化学与细胞生物学研究所）徐国良研究组和中国科学院上海营养与健康研究所邵振研究组的最新合作研究成果: “DNA cytosine methylation suppresses meiotic recombination at the sex-determining region”，该研究揭示了DNA甲基化在维持性别决定区稳定性中的重要作用。有性生殖过程中，同源重组增加了自然选择的遗传多样性，同时能够去除有害的突变。性别二态性在真核生物中广泛存在，通常由基因组中的性别决定区（sex-determining region, SDR）予以控制。为了维持性别的保真性，SDR进化出了广泛的重组抑制，这种抑制在众多物种中由不同机制调控，包括但不限于序列差异、结构重排、组蛋白修饰等等。莱茵衣藻（Chlamydomonas reinhardtii）作为一种单倍体的单细胞真核绿藻，是研究有性生殖与减数分裂的重要模式生物。衣藻的性别由mating-type locus (mt) 决定，存在两种交配型：plus与minus。MT是基因组中一段375 kb (mt+) 或211 kb (mt–) 的复杂序列，在两种交配型之间重排。此前的研究表明，重排序列对该区域的重组抑制有所贡献，但并不充分，同时两者之间的因果关系也尚不明晰。从进化的角度来看，DNA的出现早于染色体，这意味着DNA修饰的出现可能同样早于组蛋白修饰。DNA胞嘧啶甲基化（5mC）是真核生物中常见的表观遗传修饰，在多个生物学过程中发挥着重要作用。衣藻作为进化早期兼具动植物特性的生物，其性别决定区MT的高甲基化赋予了性别维持机制新的可能。研究人员首先鉴定了衣藻中负责细胞核DNA甲基化的胞嘧啶甲基转移酶，确认DNMT1 (Cre10.g461750) 是主要的维持性甲基转移酶，并通过实验室前期开发的CRISPR技术获得了多株dnmt1突变体。通过四分体分析，研究人员发现在减数分裂过程中，DNMT1的完全缺失会致使子代生存率降低以及生存谱式异常，并在MT发生非正常重组从而产生mixed-mt的异常子代。通过对重组频率的检测与统计，研究人员发现相较于WT × WT对照组，dnmt1 × dnmt1组别确实在高甲基化的MT发生相当比例的重组（对照组中频率为0）；而在常染色体区域，两组的重组频率不存在差异。染色质免疫共沉淀（ChIP-seq）结果显示，dnmt1突变藻株中，MT区域的H3K9me1修饰显著降低。为探究H3K9me1的降低与表型之间的关系，研究人员进一步构建了SET3（衣藻中产生H3K9me1修饰的主要甲基转移酶）敲除藻株，发现该基因的突变恰好能够模拟dnmt1突变藻株中H3K9me1的降低（总量与分布），同时并未对5mC水平造成影响。但在四分体分析检测中，set3 × set3组别未产生异常表型。这表明衣藻中5mC与H3K9me1是严格的上下游关系，组蛋白修饰的改变只是DNA甲基化改变的结果，并非产生表型的原因。衣藻中的这一发现使得研究人员推测，真核生物自20亿年前进化至今，DNA修饰或许行使了更多的功能。研究DNA甲基化在其他物种（如哺乳动物）中，是否对性别决定区的重组抑制有所贡献，对于探索表观遗传修饰的进化具有重要意义。综上所述，该研究发现了莱茵衣藻中DNA甲基化对交配型决定区重组抑制的重要功能，揭示了性别决定区维持的新机制，拓展了DNA甲基化的生物学功能。分子细胞卓越中心徐国良研究员、营养与健康研究所邵振研究员与分子细胞卓越中心陈辉副研究员为该论文的共同通讯作者。分子细胞卓越中心博士研究生盖彤、营养与健康研究所博士后桂秀琪、分子细胞卓越中心博士研究生徐嘉曦以及博士夏维为该论文的共同第一作者。该项工作得到了中国科学院、基金委、上海市科委等部门的经费资助，以及分子细胞卓越中心分子生物学技术平台的大力支持。 DNA甲基化抑制性别决定区的减数分裂重组文章链接： https://www.science.org/doi/10.1126/sciadv.adr2345 原文链接： https://cemcs.cas.cn/kyjz/202410/t20241011_7396237.html 本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

临床研究基因疗法

2024-10-15

·生物探索

Sci Adv | 徐国良/邵振/陈辉合作揭示DNA甲基化抑制性别决定区的减数分裂重组

引言有性生殖过程中的同源重组，增加了自然选择的遗传多样性，并能去除有害的突变。性别二态性普遍存在于真核生物中，通常由基因组中的性别决定区（sex-determining region, SDR）控制。为了维持性别的保真性，SDR进化出了广泛的重组抑制，这种抑制在众多物种中由不同机制调控，包括但不限于序列差异、结构重排、组蛋白修饰等等【1】。莱茵衣藻（Chlamydomonas reinhardtii）作为一种单倍体的单细胞真核绿藻，是研究有性生殖与减数分裂的重要模式生物。衣藻的性别由mating-type locus (mt) 决定，有两种交配型：plus与minus。MT是基因组中一段375 kb (mt+) 或211 kb (mt–) 的复杂序列【2】，在两种交配型之间重排。此前的研究表明，重排序列对该区域的重组抑制有所贡献，但并不充分【3】，同时两者的因果关系也并不明晰。从进化的角度来看，DNA早于染色体出现，意味着DNA修饰的出现可能同样早于组蛋白修饰。DNA胞嘧啶甲基化（5mC）是真核生物中常见的表观遗传修饰，在多个生物学过程中发挥着重要作用。衣藻作为进化早期兼具动植物特性的生物，其性别决定区MT的高甲基化赋予了性别维持机制新的可能。 2024年10月9日，中国科学院分子细胞科学卓越创新中心徐国良研究员、中国科学院上海营养与健康研究所邵振研究员、分子细胞科学卓越创新中心陈辉副研究员在Science Advances发表文章：DNA cytosine methylation suppresses meiotic recombination at the sex-determining region，该研究揭示了DNA甲基化在维持性别决定区稳定性中的重要作用。作者首先鉴定了衣藻中负责细胞核DNA甲基化的胞嘧啶甲基转移酶，确认DNMT1 (Cre10.g461750) 是主要的维持性甲基转移酶，并通过实验室前期开发的CRISPR技术【4】得到了多株dnmt1突变体。通过四分体分析，作者发现在减数分裂过程中，DNMT1的完全缺失会导致子代生存率的降低以及生存谱式的异常，并在MT发生非正常重组从而产生mixed-mt的异常子代。通过对重组频率的检测与统计，作者发现相较于WT × WT对照组，dnmt1 × dnmt1组别的确在高甲基化的MT发生相当比例的重组（对照组中频率为0）；而在常染色体区域，两组的重组频率并无差异。ChIP-seq结果表明，dnmt1突变藻株中，MT区域的H3K9me1修饰显著降低。为了探究H3K9me1的降低与表型之间的关系，作者进一步构建了SET3（衣藻中产生H3K9me1修饰的主要甲基转移酶）敲除藻株，发现该基因的突变恰好能模拟dnmt1突变藻株中H3K9me1的降低（总量与分布），同时并未对5mC水平造成影响。但在四分体分析检测中，set3 × set3组别并无异常表型产生。这说明衣藻中5mC与H3K9me1是严格的上下游关系，组蛋白修饰的改变只是DNA甲基化改变的结果，并非产生表型的原因。衣藻中的发现让我们有理由推测，真核生物从20亿年前进化至今，DNA修饰或许行使了更多功能。研究DNA甲基化在其他物种（如哺乳动物）中，是否贡献于性别决定区的重组抑制，将对探索表观遗传修饰的进化具有重要意义。模式图（Credit: Science Advances）综上所述，该研究发现了莱茵衣藻中DNA甲基化对交配型决定区重组抑制的重要功能，揭示了性别决定区维持的新机制，拓展了DNA甲基化的生物学功能。参考文献 1. B. L. S. Furman, D. C. H. Metzger, I. Darolti, A. E. Wright, B. A. Sandkam, P. Almeida, J. J. Shu, J. E. Mank, Sex Chromosome Evolution: So Many Exceptions to the Rules. Genome Biol Evol 12, 750-763 (2020). 2. U. Goodenough, H. Lin, J. H. Lee, Sex determination in Chlamydomonas. Semin Cell Dev Biol 18, 350-361 (2007). 3. D. Lopez, T. Hamaji, J. Kropat, P. De Hoff, M. Morselli, L. Rubbi, S. Fitz-Gibbon, S. D. Gallaher, S. S. Merchant, J. Umen, M. Pellegrini, Dynamic Changes in the Transcriptome and Methylome of Chlamydomonas reinhardtii throughout Its Life Cycle. Plant Physiol 169, 2730-2743 (2015). 4. H. Chen, Q. L. Yang, J. X. Xu, X. Deng, Y. J. Zhang, T. Liu, M. G. Rots, G. L. Xu, K. Y. Huang, Efficient methods for multiple types of precise gene-editing in Chlamydomonas. Plant J 115, 846-865 (2023). https://www.science.org/doi/epdf/10.1126/sciadv.adr2345 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

基因疗法临床结果临床1期

2024-06-27

·PRNewswire

Chroma Medicine Announces Exclusive License Agreement with the Whitehead Institute for Novel Epigenetic Editing Technology

License provides exclusive access to innovative epigenetic editors and expands the reach of Chroma's platform BOSTON, June 27, 2024 /PRNewswire/ -- Chroma Medicine, Inc. (Chroma) a genomic medicine company pioneering single-course epigenetic editing therapeutics, today announced it has entered into an exclusive license agreement with the Whitehead Institute to access intellectual property and technology developed in the lab of Chroma co-founder Jonathan Weissman, Ph.D. The novel technology called CHARM (coupled histone tail for autoinhibition release of methyltransferase) uses a compact epigenetic editing effector domain to recruit and activate endogenous DNA methyltransferases to durably silence target genes. CHARM can utilize a self-silencing mechanism to limit its duration of expression and has been shown by Dr. Weissman's lab to induce brain-wide prion protein silencing in vivo. With an aim to deliver on the transformative potential of epigenetic editing, Chroma is expanding the versatility of its platform by leveraging this new technology to rapidly advance a new class of therapeutics that harness epigenetics, nature's innate mechanism for gene regulation, to achieve unparalleled control of gene expression without cutting, nicking, or altering the DNA sequence. "This agreement is a powerful example of our deep commitment to innovation in genomic medicines," said Catherine Stehman-Breen, M.D., Chroma's Chief Executive Officer. "Adding CHARM to our arsenal of technologies strengthens our mission to bring a broad portfolio of durable epigenetic editing therapeutics to patients." About Whitehead Institute and Weissman Laboratory Whitehead Institute is a world-renowned non-profit research institute dedicated to improving human health through basic biomedical research. Whitehead Institute's mission is to forge new frontiers in science, uncovering insights today that unlock the potential of tomorrow. The Weissman Laboratory is looking at how cells ensure that proteins fold into their correct shape, as well as the role of protein misfolding in disease and normal physiology. They are also developing experimental and analytical approaches for exploring the organizational principles of biological systems and globally monitoring protein translation through ribosome profiling. About Chroma Medicine Chroma Medicine is a biotechnology company pioneering a new class of genomic medicines that harness epigenetics, nature's innate mechanism for gene regulation, to deliver precise, programmable single-course therapeutics while preserving genomic integrity. The company's modular platform enables development of medicines that can address a wide range of complex diseases, whether they require silencing, activation, or targeting multiple genes at once. Chroma was founded by the world's foremost experts in genomic research and is led by a veteran team of industry leaders and scientists with deep experience in genomic medicine, drug discovery, and development. For more information, please visit chromamedicine.com or follow us on LinkedIn and X (formerly known as Twitter). SOURCE Chroma Medicine

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