更新于：2024-05-01

ASH2L

ASH2 like, histone lysine methyltransferase complex subunit

更新于：2024-05-01

基本信息

别名

ASH2、ASH2 like, histone lysine methyltransferase complex subunit、ASH2-like protein

+ [5]

简介

Transcriptional regulator (PubMed:12670868). Component or associated component of some histone methyltransferase complexes which regulates transcription through recruitment of those complexes to gene promoters (PubMed:19131338). Component of the Set1/Ash2 histone methyltransferase (HMT) complex, a complex that specifically methylates 'Lys-4' of histone H3, but not if the neighboring 'Lys-9' residue is already methylated (PubMed:19556245). As part of the MLL1/MLL complex it is involved in methylation and dimethylation at 'Lys-4' of histone H3 (PubMed:19556245). May play a role in hematopoiesis (PubMed:12670868). In association with RBBP5 and WDR5, stimulates the histone methyltransferase activities of KMT2A, KMT2B, KMT2C, KMT2D, SETD1A and SETD1B (PubMed:21220120, PubMed:22266653).

关联

100 项与 ASH2L 相关的临床结果

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100 项与 ASH2L 相关的转化医学

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0 项与 ASH2L 相关的专利（医药）

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198

项与 ASH2L 相关的文献（医药）

2024-01-27·Cellular and molecular life sciences : CMLS

Functional role of Ash2l in oxLDL induced endothelial dysfunction and atherosclerosis.

Article

作者: Zhenghua Su ; Jinghuan Wang ; Chenxi Xiao ; Wen Zhong ; Jiayao Liu ; Xinhua Liu ; Yi Zhun Zhu

Endothelial injury and dysfunction in the artery wall fuel the process of atherosclerosis. As a key epigenetic regulator, Ash2l (Absent, small, or homeotic-Like 2) is involved in regulating vascular injury and its complications. However, the role of Ash2l in atherosclerosis has not yet been fully elucidated. Here, we found increased Ash2l expression in high-cholesterol diet-fed ApoE^-/- mice and oxidized LDL (oxLDL) treated endothelial cells (ECs). Furthermore, Ash2l promoted the scavenger receptors transcription by catalyzing histone H3 lysine 4 (H3K4) trimethylation at the promoter region of transcription factor peroxisome proliferator-activated receptor-γ (PPARγ) and triggered the activation of the pro-inflammatory nuclear factor-kappa B (NF-κB) by enhancing interaction between CD36 and toll-like receptor 4 (TLR4). Meanwhile, enhanced expression of scavenger receptors drove more oxLDL uptake by ECs. In vivo studies revealed that ECs-specific Ash2l knockdown reduced atherosclerotic lesion formation and promoted fibrous cap stability in the aorta of ApoE^-/- mice, which was partly associated with a reduced endothelial activation by suppressing scavenger receptors and the uptake of lipids by ECs. Collectively, our findings identify Ash2l as a novel regulator that mediates endothelial injury and atherosclerosis. Targeting Ash2l may provide valuable insights for developing novel therapeutic candidates for atherosclerosis.

2023-12-31·Cancer biology & therapy

CSTF2T facilitates pancreatic adenocarcinoma growth and metastasis by elevating H3K4Me1 methylation of CALB2 via ASH2L.

Article

作者: Wei Liu ; Dongwei Hu ; Jinjie Li ; Qigang Xu ; Zongjing Chen ; Bo Xu

Pancreatic adenocarcinoma (PAAD) is a major cause of mortality related to cancer worldwide. This paper dissected the functions of the CSTF2T/ASH2L/CALB2 axis in PAAD progression. CALB2 expression was assessed in PAAD tissues and cells using RT-qPCR and western blot. Subsequent to gain- and loss-of-function experiments in PAAD cells, cell apoptosis, invasion, proliferation, and migration were examined using flow cytometry, Transwell, CCK-8, and Scratch assays. Additionally, the expression of proliferation markers and apoptotic and metastasis- and invasion-related proteins was measured using western blot. The relationship among CALB2, KMT2D, ASH2L, H3K4Me1, and CSTF2T was evaluated using ChIP, RNA pull-down, RIP, and Co-IP assays. A nude mouse transplantation tumor model was established, with observation of tumor growth and metastasis. CALB2 expression was high in PAAD tissues and cells. Mechanistically, KMT2D was enriched in the CALB2 promoter, and CSTF2T bound to and upregulated ASH2L as a RNA binding protein, which was a core component of the KMT2D complex to enhance CALB2 expression through H3K4Me1 upregulation. CALB2 knockdown diminished the viability, invasion, and migration but elevated the apoptosis of PAAD cells. Likewise, CSTF2T knockdown suppressed the growth and metastasis of PAAD cells and transplanted tumors in nude mice, which was counteracted by further CALB2 overexpression. CSTF2T knockdown blocked the ASH2L/CALB2 axis to protect against PAAD growth and metastasis.

2023-12-19·Scientific reports

Sequential deregulation of histone marks, chromatin accessibility and gene expression in response to PROTAC-induced degradation of ASH2L.

Article

作者: Mirna Barsoum ; Roksaneh Sayadi-Boroujeni ; Alexander T Stenzel ; Philip Bussmann ; Juliane Lüscher-Firzlaff ; Bernhard Lüscher

The trithorax protein ASH2L is essential for organismal and tissue development. As a subunit of COMPASS/KMT2 complexes, ASH2L is necessary for methylation of histone H3 lysine 4 (H3K4). Mono- and tri-methylation at this site mark active enhancers and promoters, respectively, although the functional relevance of H3K4 methylation is only partially understood. ASH2L has a long half-life, which results in a slow decrease upon knockout. This has made it difficult to define direct consequences. To overcome this limitation, we employed a PROTAC system to rapidly degrade ASH2L and address direct effects. ASH2L loss resulted in inhibition of proliferation of mouse embryo fibroblasts. Shortly after ASH2L degradation H3K4me3 decreased with its half-life varying between promoters. Subsequently, H3K4me1 increased at promoters and decreased at some enhancers. H3K27ac and H3K27me3, histone marks closely linked to H3K4 methylation, were affected with considerable delay. In parallel, chromatin compaction increased at promoters. Of note, nascent gene transcription was not affected early but overall RNA expression was deregulated late after ASH2L loss. Together, these findings suggest that downstream effects are ordered but relatively slow, despite the rapid loss of ASH2L and inactivation of KMT2 complexes. It appears that the systems that control gene transcription are well buffered and strong effects are only beginning to unfold after considerable delay.

项与 ASH2L 相关的新闻（医药）

2023-07-26

·生物谷

中国科学院研究者们揭示了出生后神经发生以维持适当的前脑功能的关键机制

神经干细胞/祖细胞(NSPC)是一种自我更新的多潜能细胞，在胎儿发育过程中形成大脑皮层，并持续存在于成年前脑中。神经发生中NSPC产生新神经元的过程是正常大脑发育和功能所必需的。神经干细胞/祖细胞(NSPC)是一种自我更新的多潜能细胞，在胎儿发育过程中形成大脑皮层，并持续存在于成年前脑中。神经发生中NSPC产生新神经元的过程是正常大脑发育和功能所必需的。终生持续的神经发生发生在海马齿状回的颗粒下带(SGZ)，并被认为与认知过程和神经系统疾病有关。然而，关于NSPC在出生后神经发生过程中决定命运和功能的调控机制，仍有许多需要了解。 NSPC在出生后阶段的维持和分化受到复杂的分子网络的严格控制。更好地理解这些在出生后神经发生中的调控机制可能会为深入阐明大脑的可塑性提供更多的线索，为实现NSPC治疗神经系统疾病的潜力提供更多的线索。图片来源: https://doi-org.libproxy1.nus.edu.sg/10.1038/s41418-023-01189-y 近日，来自中国科学院的研究者们在Cell Death & Differentiation杂志上发表了题为“ASH2L regulates postnatal neurogenesis through Onecut2-mediated inhibition of TGF-β signaling pathway”的文章，该研究揭示了ASH_2通过抑制转化生长因子-β信号通路调控生后神经发生。神经干细胞/祖细胞(NSPC)在神经发生的不同阶段都需要增殖和分化的能力。神经发生的调节障碍会导致许多神经疾病，如智力残疾、自闭症和精神分裂症。然而，这种调控在神经发生中的内在机制仍然知之甚少。在本研究中，研究者报告了组蛋白甲基转移酶多聚体复合体的核心成分Ash21(缺失的、小的或同源异型盘样2)在出生后神经发生过程中对NSPC命运的决定是必不可少的。NSPC中Ash21基因的缺失会损害NSPC的增殖和分化能力，导致成年出生的海马神经元树突状突起的简化和认知能力的下降。 RNA测序数据显示，Ash21主要调控细胞命运指定和神经元结合。此外，研究者还鉴定了以二价组蛋白修饰为特征的ASH2 L下游的主要靶标ONECUT2，并证明了ONECUT2的结构性表达可以恢复成年Ash2基因缺陷小鼠NSPC的缺陷增殖和分化。重要的是，研究者发现ONECKUT 2在NSPC中调节转化生长因子-β信号，并且用转化生长因子-β抑制剂治疗可以纠正缺乏Ash21的NSPC的表型。总而言之，本研究发现揭示了ASH2L-ONECUT2-转化生长因子-β信号轴，它介导了出生后神经发生以维持适当的前脑功能。抑制转化生长因子-β信号通路恢复Ash21基因缺陷小鼠成体神经发生缺陷图片来源: https://doi-org.libproxy1.nus.edu.sg/10.1038/s41418-023-01189-y 综上所述，本研究揭示了Ash21是调节NSPC增殖和分化以及正常认知功能的关键调节因子。研究者表明，Ash21、OC2和转化生长因子-β形成了一个调控网络，控制着NSPC细胞命运的决定。这些发现代表着朝着揭开NSPC生物学基础的分子机制迈出的重要一步，并可能为干细胞治疗修复受损的大脑提供新的再生潜力。（生物谷 Bioon.com）参考文献 Ya-Jie Xu et al. ASH2L regulates postnatal neurogenesis through Onecut2-mediated inhibition of TGF-β signaling pathway. Cell Death Differ. 2023 Jul 11. doi: 10.1038/s41418-023-01189-y.

2022-09-15

·生物谷

iScience：陈勇团队揭示DPY30促进MLL复合物甲基转移酶活性的分子机制

H3K4甲基化修饰对增强子活性调控、转录激活和细胞命运决定起关键作用，其异常会导致多种白血病和恶性肿瘤的发生。H3K4甲基化修饰主要是由MLL家族蛋白催化产生。 H3K4甲基化修饰对增强子活性调控、转录激活和细胞命运决定起关键作用，其异常会导致多种白血病和恶性肿瘤的发生。H3K4甲基化修饰主要是由MLL家族蛋白催化产生。MLL家族蛋白自身的甲基转移酶活性很低，需要与WDR5、RBBP5、ASH2L、DPY30等调节亚基形成复合物，才能有效发挥酶活。WDR5、RBBP5、ASH2L等亚基参与调控MLL蛋白酶活的分子机制在过去得到了充分的研究，但DPY30作为复合物中最小的蛋白（只有99个氨基酸）其发挥的作用和调节机制尚不明确。近日，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）陈勇研究组在 iScience 期刊发表了题为：DPY30 acts as an ASH2L-specific stabilizer to stimulate the enzyme activity of MLL family methyltransferases on different substrates 的研究论文，揭示了DPY30促进MLL复合物甲基转移酶活性的分子机制。在这项研究中，研究团队发现DPY30可以不同程度地增强MLL1复合物在不同底物上的活性。在核小体底物上，DPY30能提高MLL复合物的催化效率逾27倍；在组蛋白多肽、H3或组蛋白八聚体水平上，DPY30仅能提高催化效率约1.8倍。研究团队继而通过交联质谱、小角散射、结构预测、动力学模拟等多种方法阐明了DPY30通过多种机制来调控复合物的甲基转移酶活性。首先，DPY30与ASH2L的多个结构域结合，增加了ASH2L的结构紧致性和热稳定性；DPY30稳定后的ASH2L与RBBP5结合力增强，促进MLL1复合物组装形成一个更紧凑和更稳定的复合物，导致DPY30可以微调MLL1复合物在组蛋白多肽、H3、组蛋白八聚体上的酶活。其次，DPY30稳定后的ASH2L获得了与组蛋白H3 N端尾巴（1-40）和核小体DNA结合的新的作用界面，确保核小体H3的尾部准确且稳定地进入MLLSET的催化口袋，从而极大地促进MLL1复合物甲基化核小体的活性，揭示了DPY30特异性促进MLL1复合物在核小体上酶活的机制。 DPY30促进MLL复合物甲基转移酶活性的分子机制 DPY30在多种癌症中高表达，之前的研究表明DPY30的促癌效应与H3K4甲基化修饰相关。在癌细胞中敲低DPY30，H3K4甲基化修饰水平降低，癌细胞增殖减慢；回补DPY30，H3K4甲基化修饰水平增加，癌细胞增殖增快。因此，该研究中揭示的DPY30调控MLL复合物甲基转移酶活性的分子机制可以为理解相关癌症发病机制提供理论基础，以及为相关癌症的治疗提供新的设计思路和设计靶点。中科院分子细胞卓越中心博士生赵利杰为论文第一作者，陈勇研究员为该论文的通讯作者。该研究工作获得中科院战略性先导计划和国家自然科学基金委的经费资助。该研究得到张江实验室国家蛋白质科学研究（上海）设施BL19U2小角散射线站、质谱分析系统和规模化蛋白质制备系统的支持和帮助。