更新于：2024-09-19

KMT2E

更新于：2024-09-19

基本信息

别名

HDCMC04P、Inactive histone-lysine N-methyltransferase 2E、Inactive lysine N-methyltransferase 2E

+ [7]

简介

Associates with chromatin regions downstream of transcriptional start sites of active genes and thus regulates gene transcription (PubMed:23629655, PubMed:24130829, PubMed:23798402). Chromatin interaction is mediated via the binding to tri-methylated histone H3 at 'Lys-4' (H3K4me3) (PubMed:24130829, PubMed:23798402). Key regulator of hematopoiesis involved in terminal myeloid differentiation and in the regulation of hematopoietic stem cell (HSCs) self-renewal by a mechanism that involves DNA methylation (By similarity). Also acts as an important cell cycle regulator, participating in cell cycle regulatory network machinery at multiple cell cycle stages including G1/S transition, S phase progression and mitotic entry (PubMed:14718661, PubMed:18573682, PubMed:19264965, PubMed:23629655). Recruited to E2F1 responsive promoters by HCFC1 where it stimulates tri-methylation of histone H3 at 'Lys-4' and transcriptional activation and thereby facilitates G1 to S phase transition (PubMed:23629655). During myoblast differentiation, required to suppress inappropriate expression of S-phase-promoting genes and maintain expression of determination genes in quiescent cells (By similarity). Cellular ligand for NCR2/NKp44, may play a role as a danger signal in cytotoxicity and NK-cell-mediated innate immunity.

关联

100 项与 KMT2E 相关的临床结果

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100 项与 KMT2E 相关的转化医学

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0 项与 KMT2E 相关的专利（医药）

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120

项与 KMT2E 相关的文献（医药）

2024-06-01·European Journal of Medical Genetics

Penetrance, variable expressivity and monogenic neurodevelopmental disorders

Article

作者: Goldenberg, Alice ; Gerard, Bénédicte ; Bilan, Frédéric ; Isidor, Bertrand ; Bauer, Peter ; Vitobello, Antonio ; Saugier-Veber, Pascale ; Mau-Them, Frédéric Tran ; Pasquier, Laurent ; Nizon, Mathilde ; Lecoquierre, François ; Zweier, Christiane ; de Masfrand, Servane ; Piard, Juliette ; le Guyader, Gwenaël ; Faivre, Laurence ; Cogné, Benjamin ; Piton, Amélie ; Nicolas, Gaël ; Bournez, Marie ; Bézieau, Stéphane ; Deb, Wallid

PURPOSEIncomplete penetrance is observed for most monogenic diseases. However, for neurodevelopmental disorders, the interpretation of single and multi-nucleotide variants (SNV/MNVs) is usually based on the paradigm of complete penetrance.METHODFrom 2020 to 2022, we proposed a collaboration study with the French molecular diagnosis for intellectual disability network. The aim was to recruit families for whom the index case, diagnosed with a neurodevelopmental disorder, was carrying a pathogenic or likely pathogenic variant for an OMIM morbid gene and inherited from an asymptomatic parent. Grandparents were analyzed when available for segregation study.RESULTSWe identified 12 patients affected by a monogenic neurodevelopmental disorder caused by likely pathogenic or pathogenic variant (SNV/MNV) inherited from an asymptomatic parent. These genes were usually associated with de novo variants. The patients carried different variants (1 splice-site variant, 4 nonsense and 7 frameshift) in 11 genes: CAMTA1, MBD5, KMT2C, KMT2E, ZMIZ1, MN1, NDUFB11, CUL3, MED13, ARID2 and RERE. Grandparents have been tested in 6 families, and each time the variant was confirmed de novo in the healthy carrier parent.CONCLUSIONIncomplete penetrance for SNV and MNV in neurodevelopmental disorders might be more frequent than previously thought. This point is crucial to consider for interpretation of variants, family investigation, genetic counseling, and prenatal diagnosis. Molecular mechanisms underlying this incomplete penetrance still need to be identified.

2024-06-01·Annals of Translational Medicine

A HIF-2α-dependent KMT2E-AS1/KMT2E axis orchestrates endothelial epigenetic and metabolic dysfunction in pulmonary hypertension

Communications

作者: Boucherat, Olivier ; Bonnet, Sébastien ; Potus, François ; Lemay, Sarah-Eve ; Provencher, Steeve

2024-06-01·Genes, Brain and Behavior

Human‐specific insights into candidate genes and boosted discoveries of novel loci illuminate roles of neuroglia in reading disorders

Article

作者: Ma, Shaowei ; Fu, Bo ; Guo, Hui ; Wei, Wen-Hua ; Song, Ranran

AbstractReading disorders (RD) are human‐specific neuropsychological conditions associated with decoding printed words and/or reading comprehension. So far only a handful of candidate genes segregated in families and 42 loci from genome‐wide association study (GWAS) have been identified that jointly provided little clues of pathophysiology. Leveraging human‐specific genomic information, we critically assessed the RD candidates for the first time and found substantial human‐specific features within. The GWAS candidates (i.e., population signals) were distinct from the familial counterparts and were more likely pleiotropic in neuropsychiatric traits and to harbor human‐specific regulatory elements (HSREs). Candidate genes associated with human cortical morphology indeed showed human‐specific expression in adult brain cortices, particularly in neuroglia likely regulated by HSREs. Expression levels of candidate genes across human brain developmental stages showed a clear pattern of uplifted expression in early brain development crucial to RD development. Following the new insights and loci pleiotropic in cognitive traits, we identified four novel genes from the GWAS sub‐significant associations (i.e., FOXO3, MAPT, KMT2E and HTT) and the Semaphorin gene family with functional priors (i.e., SEMA3A, SEMA3E and SEMA5B). These novel genes were related to neuronal plasticity and disorders, mostly conserved the pattern of uplifted expression in early brain development and had evident expression in cortical neuroglial cells. Our findings jointly illuminated the association of RD with neuroglia regulation—an emerging hotspot in studying neurodevelopmental disorders, and highlighted the need of improving RD phenotyping to avoid jeopardizing future genetic studies of RD.

项与 KMT2E 相关的新闻（医药）

2024-02-11

·药明康德

1月，11款创新靶点值得关注（附PDF下载）

▎药明康德内容团队编辑近三年，FDA批准的新药里具有创新机制的药物占比均超过一半。由于基于靶点的筛选是过去几十年新药研发的主要方式，这些创新药物的起点往往都是相关靶点的发现和验证。这也意味着医药行业的不断创新仰赖对新靶点及其生物学机理的不断挖掘。正如多位嘉宾在药明康德BOLD系列论坛中指出的那样，很多“容易的靶点”已经转化为了创新疗法，如今的新药发现公司需要探索更为复杂、更难治疗的疾病，而这个过程依赖于对于靶点及其生物学的深度认知，也需要前沿科技的更多进步。药明康德内容团队盘点了2024年1月发布于国际知名科研期刊中的潜力靶点，以供各位医药界的朋友们参考。这些潜力靶点涵盖癌症、中枢神经系统疾病、心血管、罕见病等多个方向，有的是新的肿瘤合成致死靶点，有的为罕见病提供了全新治疗方案，都具有潜在转化价值。在这篇文章中，我们优选3个值得关注的靶点做详细报道。点击“阅读原文”或扫描文中二维码并填写文中调查问卷，留下您的邮箱，即可申请获得完整11个靶点列表。▲点击“阅读原文”或扫描以上二维码并填写问卷，以申请获得《2024年1月潜在可转化创新靶点》分析报告靶点：APOE3ch应用：诠释一种拮抗阿尔茨海默症的基因突变机理期刊 / PMID：《细胞》 / 38086389发现：一个病例报告研究显示APOE3 Christchurch（APOE3ch）突变纯合携带者对PSEN1-E280A突变引起的常染色体显性阿尔茨海默病（AD）具有抵抗力。本论文的研究人员构建了人源化APOE3ch敲入小鼠。与病例报告类似，在该小鼠模型里APOE3ch表达导致外周血脂异常和斑块相关的tau病理学显著减少。淀粉样蛋白反应减少与斑块周围的小胶质细胞反应增强。这些结果显示APOE3ch影响小胶质细胞对Aβ斑块的反应，抑制Aβ诱导的tau蛋白播种和扩散，也为Aβ诱导的tau蛋白病变提供了新的药物研发思路。▲APOE3ch表达导致外周血脂异常和斑块相关的tau病理学显著减少（图片来源：参考资料[1]）靶点：B3GALT6应用：清除导致复发的难治性残留肿瘤细胞期刊 / PMID：Cancer Cell / 38065100发现：无法治愈的复发是乳腺癌等肿瘤致死的主要原因，这种复发被认为来自休眠的、难治性残留肿瘤细胞（RTC）播种。因此，了解RTC存活的机制对改善癌症治疗至关重要。在这篇论文里，作者通过体内CRISPR-Cas9筛选细胞休眠相关的候选基因，确定半乳糖基转移酶B3GALT6是RTC适应性的功能调节因子。B3GALT6是糖胺聚糖（glycosaminoglycan，GAG）与蛋白质连接，生成蛋白聚糖所必需的代谢酶，种系功能缺失会导致骨骼发育不良。而研究人员发现B3GALT6介导的硫酸乙酰肝素GAG生物合成可预测肿瘤患者预后不良。机理上，B3GALT6-硫酸乙酰肝素/HS6ST1-乙酰肝素6-O-硫酸化/FGF1-FGFR2信号通路能提高休眠RTC的存活率，促进复发。该研究表明B3GALT6与癌症有关，抑制B3GALT6相关通路，包括抑制FGFR2是一种潜在的根除休眠RTC，预防复发的手段。▲B3GALT6在微环境诱导的肿瘤休眠模型中促进肿瘤细胞存活及生长（图片来源：参考资料[2]）靶点：KMT2E应用：肺动脉高压关键靶点期刊 / PMID：Science Translational Medicine / 38198571发现：肺动脉高压（PAH）是一种由依赖缺氧诱导因子（HIF）的血管功能障碍驱动的疾病，HIF-2α促进邻近基因KMT2E-AS1和KMT2E的表达。在功能上，KMT2E-AS1是一种长非编码RNA（lncRNA），可稳定KMT2E蛋白，增加表观遗传组蛋白H3的4号位赖氨酸三甲基化（H3K4me3），驱动依赖HIF-2α的代谢和致病性内皮活性。该lncRNA信号通路还增加了表观遗传、转录和转录后环境中的HIF-2α表达，从而形成正反馈，进一步增强HIF-2α活性。在本研究中，作者在PAH患者队列以及全球荟萃分析中确定了KMT2E内含子内的一个单核苷酸变异（SNV）rs73184087与PAH疾病的遗传风险相关。该SNV特定的等位基因与HIF-2α形成关联，参与长程染色质相互作用，并在缺氧细胞中诱导KMT2E-AS1和KMT2E的相互作用。体内实验中，KMT2E-AS1缺失可以保护小鼠免受PAH侵害，通过药物抑制大鼠组蛋白甲基化也有相同作用。而与之对应的，强制这一lncRNA表达会形成更严重的疾病表现。因此，KMT2E-AS1/KMT2E介导HIF-2α病理，是肺动脉高压的关键临床靶点。▲KMT2E-AS1诱导HIF-2α激活并阻止HIF-2α降解，从而驱动内皮病理表型（图片来源：参考资料[3]）潜在靶点众多，限于篇幅，本文不一一进行介绍。请点击“阅读原文”或扫描文中二维码并填写文中调查问卷，留下您的邮箱，即可申请获得完整靶点列表。▲点击“阅读原文”或扫描以上二维码并填写问卷，以申请获得《2024年1月潜在可转化创新靶点》分析报告大家都在看▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Chen, Yun et al. “APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread.” Cell vol. 187,2 (2024): 428-445.e20. doi:10.1016/j.cell.2023.11.029[2] Sreekumar, Amulya et al. “B3GALT6 promotes dormant breast cancer cell survival and recurrence by enabling heparan sulfate-mediated FGF signaling.” Cancer cell vol. 42,1 (2024): 52-69.e7. doi:10.1016/j.ccell.2023.11.008[3] Tai, Yi-Yin et al. “Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension.” Science translational medicine vol. 16,729 (2024): eadd2029. doi:10.1126/scitranslmed.add2029免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新