更新于：2024-09-19

RBBP5

更新于：2024-09-19

基本信息

别名

RB binding protein 5, histone lysine methyltransferase complex subunit、RBBP-5、RBBP5

+ [4]

简介

In embryonic stem (ES) cells, plays a crucial role in the differentiation potential, particularly along the neural lineage, regulating gene induction and H3 'Lys-4' methylation at key developmental loci, including that mediated by retinoic acid (By similarity). Does not affect ES cell self-renewal (By similarity). Component or associated component of some histone methyltransferase complexes which regulates transcription through recruitment of those complexes to gene promoters (PubMed:19131338). As part of the MLL1/MLL complex, involved in mono-, di- and trimethylation at 'Lys-4' of histone H3 (PubMed:19556245). Histone H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation (PubMed:19556245). In association with ASH2L and WDR5, stimulates the histone methyltransferase activities of KMT2A, KMT2B, KMT2C, KMT2D, SETD1A and SETD1B (PubMed:22266653, PubMed:21220120).

关联

100 项与 RBBP5 相关的临床结果

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100 项与 RBBP5 相关的转化医学

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0 项与 RBBP5 相关的专利（医药）

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158

项与 RBBP5 相关的文献（医药）

2024-12-01·Molecular Genetics and Genomics

lncCPSET1 acts as a scaffold for MLL2/COMPASS to regulate Bmp4 and promote the formation of chicken primordial germ cells

Article

作者: Zuo, Qisheng ; Jin, Kai ; Li, Bichun ; Zhang, Chen ; Ding, Ying

Primordial germ cells (PGCs) are the ancestors of female and male germ cells. Recent studies have shown that long non-coding RNA (lncRNA) and histone methylation are key epigenetic factors affecting PGC formation; however, their joint regulatory mechanisms have rarely been studied. Here, we explored the mechanism by which lncCPSET1 and H3K4me2 synergistically regulate the formation of chicken PGCs for the first time. Combined with chromatin immunoprecipitation (CHIP) sequencing and RNA-seq of PGCs transfected with the lncCPSET1 overexpression vector, GO annotation and KEGG enrichment analysis revealed that Wnt and TGF-β signaling pathways were significantly enriched, and Fzd2, Id1, Id4, and Bmp4 were identified as candidate genes. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) showed that ASH2L, DPY30, WDR5, and RBBP5 overexpression significantly increased the expression of Bmp4, which was up-regulated after lncCPSET1 overexpression as well. It indicated that Bmp4 is a target gene co-regulated by lncCPSET1 and MLL2/COMPASS. Interestingly, co-immunoprecipitation results showed that ASH2L, DPY30 and WDR5 combined and RBBP5 weakly combined with DPY30 and WDR5. lncCPSET1 overexpression significantly increased Dpy30 expression and co-immunoprecipitation showed that interference/overexpression of lncCPSET1 did not affect the binding between the proteins in the complexes, but interference with lncCPSET1 inhibited DPY30 expression, which was confirmed by RNA immunoprecipitation that lncCPSET1 binds to DPY30. Additionally, CHIP-qPCR results showed that DPY30 enriched in the Bmp4 promoter region promoted its transcription, thus promoting the formation of PGCs. This study demonstrated that lncCPSET1 and H3K4me2 synergistically promote PGC formation, providing a reference for the study of the regulatory mechanisms between lncRNA and histone methylation, as well as a molecular basis for elucidating the formation mechanism of PGCs in chickens.

2024-07-12·Science Advances

N-terminal acetylation of Set1-COMPASS fine-tunes H3K4 methylation patterns

Article

作者: Oh, Goo Taeg ; Kim, Seon-Young ; Han, Dohyun ; Dan, Kisoon ; Cho, Yong-Joon ; Oh, Junsoo ; Woo, Hyeonju ; Kim, TaeSoo ; Lee, Jung-Shin

H3K4 methylation by Set1-COMPASS (complex of proteins associated with Set1) is a conserved histone modification. Although it is critical for gene regulation, the posttranslational modifications of this complex that affect its function are largely unexplored. This study showed that N-terminal acetylation of Set1-COMPASS proteins by N-terminal acetyltransferases (NATs) can modulate H3K4 methylation patterns. Specifically, deleting NatA substantially decreased global H3K4me3 levels and caused the H3K4me2 peak in the 5′ transcribed regions to shift to the promoters. NatA was required for N-terminal acetylation of three subunits of Set1-COMPASS: Shg1, Spp1, and Swd2. Moreover, deleting Shg1 or blocking its N-terminal acetylation via proline mutation of the target residue drastically reduced H3K4 methylation. Thus, NatA-mediated N-terminal acetylation of Shg1 shapes H3K4 methylation patterns. NatB also regulates H3K4 methylation, likely via N-terminal acetylation of the Set1-COMPASS protein Swd1. Thus, N-terminal acetylation of Set1-COMPASS proteins can directly fine-tune the functions of this complex, thereby substantially shaping H3K4 methylation patterns.

2024-07-01·Genetics in Medicine

Loss-of-function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly

Article

作者: Silverman, Edwin K. ; Martin, Beth A. ; Isasi, Rosario ; Sinsheimer, Janet S. ; LeBlanc, Kimberly ; McCray, Alexa T. ; Kohane, Isaac S. ; Gochuico, Bernadette ; Palmer, Christina G.S. ; Adams, David R. ; Barel, Ortal ; Fogel, Brent L. ; Mulvihill, John J. ; Jean-Marie, Orpa ; Loo, Sandra K. ; Vogel, Tiphanie P. ; Westerfield, Monte ; Grajewski, Alana ; Mahoney, Rachel ; Sacco, Ralph ; Lanpher, Brendan C. ; McGee, Elisabeth ; Sampson, Jacinda B. ; Wenger, Tara ; Jobanputra, Vaidehi ; Iascone, Maria ; Toro, Camilo ; Gahl, William A. ; Might, Matthew ; Sacharow, Stephanie ; Lanza, Ian R. ; Jarvik, Gail P. ; Tan, Queenie K.G. ; Spillmann, Rebecca C. ; Raskind, Wendy ; Bernstein, Jonathan A. ; Moore, Ryan M. ; Bamshad, Michael ; Potocki, Lorraine ; Viskochil, Dave ; Carrasquillo, Olveen ; Butte, Manish J. ; Liu, Xue Zhong ; Mao, Rong ; Walley, Nicole M. ; Lam, Christina ; D’Souza, Precilla ; Wan, Jijun ; Lalani, Seema R. ; Telischi, Fred ; Schedl, Timothy ; Posey, Jennifer E. ; Lam, Byron ; Worley, Kim ; Longo, Nicola ; Tarakad, Arjun ; Stoler, Joan M. ; Kilich, Gonench ; Renteria, Genecee ; Ruzhnikov, Maura ; Carvhalo Neto, George D. ; Baldridge, Dustin ; Earl, Dawn ; Saillour, Virginie ; Jangam, Sharayu V. ; Moretti, Paolo ; Dorrani, Naghmeh ; Xue, Han ; Cobban, Laurel A. ; Mariani, Milena ; Beggs, Alan H. ; McConkie-Rosell, Allyn ; Behrens, Edward ; Krakow, Deborah ; Bennett, Jimmy ; Thorson, Willa ; Botto, Lorenzo ; Shin, Jimann ; Cunningham, Michael ; Keren, Boris ; Martinez-Agosto, Julian A. ; Wheeler, Matthew T. ; Pusey Swerdzewski, Barbara N. ; Kaitryn, Emerald ; Wahl, Colleen E. ; Sullivan, Jennifer A. ; Zuchner, Stephan ; Solomon, Ben ; Chao, Hsiao-Tuan ; Emrick, Lisa T. ; Cope, Heidi ; Martin, Martin G. ; Huang, Alden ; Rodan, Lance H. ; Allworth, Aimee ; Kohler, Jennefer N. ; Davis, Joie ; Stergachis, Andrew ; Martínez-Agosto, Julian A. ; Briere, Lauren C. ; Hom, Jason ; Ashley, Euan A. ; Oglesbee, Devin ; Forghani, Irman ; Peter Chang, Ta Chen ; Burke, Elizabeth A. ; Xiao, Changrui ; Manolio, Teri A. ; Dasari, Surendra ; Loscalzo, Joseph ; Dai, Hongzheng ; Hubshman, Monika Weisz ; Sutton, Shirley ; Cole, F. Sessions ; Clark, Gary D. ; Ungar, Rachel A. ; Coggins, Matthew ; Raper, Anna ; Lee, Brendan H. ; Falk, Marni ; Douine, Emilie D. ; MacRae, Calum A. ; Pallais, J. Carl ; Hutchison, Sarah ; Cogan, Joy D. ; Marwaha, Shruti ; Horike-Pyne, Martha ; Andrews, Ashley ; Jarvik, Jeffrey ; Yamamoto, Shinya ; Wolfe, Lynne A. ; Mirzaa, Ghayda ; Malicdan, May Christine V. ; High, Frances ; Sullivan, Kathleen ; Wambach, Jennifer ; Jay, Kristy L. ; Doherty, Daniel ; Orengo, James P. ; Glass, Ian ; Halley, Meghan C. ; Bademci, Guney ; Byers, Peter ; Marth, Gabor ; Dipple, Katrina ; Holm, Ingrid A. ; Kiley, Dana ; Jayadev, Suman ; Acosta, Maria T. ; Smith, Kevin S. ; Liu, Pengfei ; Bican, Anna ; Byrd, William E. ; Hadley, Don ; Korrick, Susan ; Barbouth, Deborah ; Mah-Som, Annelise Y. ; Walker, Melissa ; Cassini, Thomas ; Maduro, Valerie V. ; Bacino, Carlos A. ; Rossignol, Francis ; Levitt, Roy ; Morava, Eva ; Scott, Daryl A. ; Burrage, Lindsay C. ; Tifft, Cynthia J. ; Rosenthal, Elizabeth ; Huang, Alden Yen-Wen ; Sisco, Kathy ; Hamid, Rizwan ; Bohnsack, John ; Rives, Lynette ; Phillips, John A. ; Macnamara, Ellen F. ; Krasnewich, Donna M. ; Alvey, Justin ; Alvarez, Raquel, L. ; Fisher, Paul G. ; Yang, John ; Dayal, Jyoti G. ; Corona, Rosario ; Tekin, Mustafa ; Pak, Stephen ; Nieves-Rodriguez, Shirley ; Chorin, Odelia ; Hayes, Nichole ; Kravets, Elijah ; Schaechter, Judy ; Sweetser, David A. ; Craigen, William J. ; Wegner, Daniel ; Urv, Tiina K. ; Introne, Wendy ; Miller, Danny ; Berry, Gerard T. ; Pace, Laura ; Chanprasert, Sirisak ; Balasubramanyam, Ashok ; Dell'Angelica, Esteban C. ; McCauley, Jacob ; Zhang, Zhe ; Costin, Carrie ; Bellen, Hugo J. ; Blue, Elizabeth ; Papp, Jeanette C. ; Maghiro, Audrey Stephannie ; Whitlock, Jordan ; Robertson, Amy K. ; Shelkowitz, Emily ; Izumi, Kosuke ; Crouse, Andrew B. ; Mamounas, Laura A. ; Huang, Jing ; Tran, Alyssa A. ; Nelson, Stanley F. ; Ketkar, Shamika ; Wener, Mark ; Solnica-Krezel, Lilianna ; Goddard, Page C. ; Ward, Patricia A. ; Colley, Heather A. ; Hassey, Kelly ; Eckstein, David J. ; Maas, Richard L. ; Seto, Elaine ; Smith, Edward C. ; Eng, Christine M. ; Saporta, Mario ; Tabor, Holly K. ; Rajabi, Farrah ; Wangler, Michael F. ; Wang, Lee-kai ; Bale, Jim ; Velinder, Matt ; Rao, Deepak A. ; Beck, Anita ; Rosenfeld, Jill A. ; Fieg, Elizabeth L. ; Bivona, Stephanie ; Carey, John ; Sheppeard, Sam ; Hing, Anne ; Sybert, Virginia ; Bonner, Devon ; Coakley, Terra R. ; Vanderver, Adeline ; Bayrak-Toydemir, Pinar ; Kanca, Oguz ; Mignot, Cyril ; Rothschild, Annick ; Lewis, Richard A. ; Quinlan, Aaron ; Chinn, Ivan ; Schoch, Kelly ; Novacic, Donna ; Bejerano, Gill ; Godfrey, Rena A. ; Parker, Neil H. ; Reuter, Chloe M. ; Brown, Gabrielle ; Kobren, Shilpa N. ; Nakano-Okuno, Mariko ; Doss, Argenia L. ; Tan, Amelia L.M. ; Shashi, Vandana ; Huang, Yue ; Hisama, Fuki M. ; Marom, Ronit

PURPOSEEpigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 (H3K4) and has not been implicated in human disease.METHODSWe identify five unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and two missense variants were identified in probands with neurodevelopmental symptoms including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models.RESULTSBoth missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the interface between RBBP5 and the nucleosome. In Drosophila, overexpression analysis identifies partial loss-of-function mechanisms when the variants are expressed using the fly Rbbp5 or human RBBP5 cDNA. Loss of Rbbp5 leads to a reduction in brain size. The human reference or variant transgenes fail to rescue this loss and expression of either missense variant in an Rbbp5 null background results in a less severe microcephaly phenotype than the human reference, indicating both missense variants are partial loss-of-function alleles.CONCLUSIONHaploinsufficiency of RBBP5 observed through de novo null and hypomorphic loss-of-function variants is associated with a syndromic neurodevelopmental disorder.

项与 RBBP5 相关的新闻（医药）

2023-03-25

·生物探索

Cell Research：揭示 H3K4me2/3 直接调控基因转录的机制

基因表达的精准调控，对机体发育和细胞的各种生理功能的维持至关重要。真核生物基因的转录主要分为转录起始（initiation）、暂停-释放（pausing-release）、延伸（elongation）和终止（termination）四个步骤，转录进程的顺利进行与DNA修饰、组蛋白修饰和RNA修饰等表观遗传修饰高度相关。组蛋白修饰（histone modification）是指组蛋白在相关酶催化下发生甲基化、乙酰化、磷酸化、泛素化和ADP核糖基化等动态修饰的过程，它可通过招募效应蛋白来改变染色质的开放或凝聚的状态，进而调控基因的表达。组蛋白H3第4位赖氨酸的甲基化修饰（H3K4）在进化上高度保守，是被研究最多的组蛋白修饰。2023年3月15日，复旦大学生物医学研究院陈飞团队在Cell Research上发表了题为H3K4me2/3 modulate the stability of RNA polymerase II pausing的研究论文，发现H3K4me2/3在细胞内是通过维持暂停Pol II（paused Pol II）在近端启动子区的稳定而促进基因激活，而H3K4me2/3对转录起始没有明显的调控作用。本研究中涉及所有测序服务均由安诺优达提供。研究结果为了研究H3K4甲基化修饰对转录是否具有直接的调控作用，研究人员在小鼠胚胎干细胞（mESCs）中利用CRISPR-Cas9系统构建了FKBP12F36V-RBBP5和DPY30（RBBP5-dTAG和DPY30-dTAG）细胞系，通过对内源蛋白进行快速降解，发现随着蛋白降解时间的延长，约12-24小时可清除H3K4me3和H3K4me2，需要更长的时间才可能清除H3K4me1，表明H3K4me2/3相对于H3K4me1更加动态（图1）。ChIP-Rx结果显示蛋白降解6小时后H3K4me3在全基因组上的分布均显著降低，大部分H3K4me2在全基因组上的分布也显著降低，变化趋势与WB显示的结果一致。图1 RBBP5蛋白快速降解后组蛋白修饰变化谱为了探究H3K4me2/3的减少是否会影响转录，研究人员在蛋白降解不同时间的mRBBP5-dTAG小鼠胚胎干细胞系中进行Pol II ChIP-Rx，结果表明H3K4me2/3具有维持启动子区Pol II稳定的作用。为了回答H3K4me2/3具体维持哪类Pol II的稳定，研究人员用Triptolide处理RBBP5蛋白降解12小时后的细胞，发现PIC Pol II在启动子区的分布没有减少，揭示了H3K4me2/3具有维持启动子区暂停Pol II稳定的作用。图2 H3K4me2/3对基因转录调控的作用总结长久以来，人们认为H3K4me3通过招募TFIID来促进转录起始复合物（PIC）的组装，进而促进基因转录。该工作利用小鼠胚胎干细胞模型研究了H3K4me2/3对基因转录的直接调控作用，回答了长期困扰领域的问题。发现H3K4me2/3不影响转录的起始或调控转录的暂停-释放，而是通过维持暂停Pol II在近端启动子区稳定的新颖机制来调控转录。为研究H3K4me2/3在细胞命运决定和病变进展的作用机制提供全新视角。校对|木子久End 往期精选围观 ‍道阻且长：投入20年，礼来阿尔兹海默病药物Solanezumab宣告失败退场！热文首个长新冠预防药物，“神药”二甲双胍可将新冠后遗症风险降低42%！热文每天少使用15分钟手机，可增强免疫、改善睡眠！热文Cell揭秘免疫系统 “命案现场清理师”的前世今生，有望破解自身免疫性疾病难题热文 430亿美元！辉瑞拟收购ADC领域龙头企业Seagen点击“阅读原文”，了解更多~

临床结果临床终止

2023-03-04

·生物谷

破解20年难题！《Nature》重磅：揭示调控细胞内基因转录的“红绿灯”机制！

假如基因是一条条设定好的马路，那么基因的转录过程就像是车辆在路上行驶，路况瞬息万变。未改变DNA序列的表观遗传修饰则如同道路上附属的信号灯、指示牌、加油站，调控着车辆的运行。如若信号灯出现了故障，交通就容易失控；如若基因的表观遗传修饰失调，基因的转录则会变得紊乱，进而引发癌症等疾病。在诸多表观遗传的修饰方式中，组蛋白的甲基化修饰与基因的转录调控息息相关，其中组蛋白H3赖氨酸K4被广泛研究。三甲基化的组蛋白H3赖氨酸K4（H3K4 me3）对正常细胞发育至关重要，且与白血病、乳腺癌、肠癌和胰腺癌联系紧密。因此，了解它如何在正常细胞中发挥作用也可以为癌症的发展提供新的思路。但直到现在，科学家们仍对它的作用缺乏了解。3月1日发表在《Nature》杂志上的一项重要新研究就揭示了H3K4me3控制细胞内基因转录的“红绿灯”机制【1】。在这项研究中，伦敦癌症研究所（The Institute of Cancer Research, London）的科学家们利用小鼠干细胞和复杂的遗传和生化实验，发现三甲基化的组蛋白H3赖氨酸K4（H3K4 me3）能够确保基因在正确的时间以可控的方式被转录和激活，就像一组信号灯在繁忙的道路上调节汽车的流量。通过调节 RNA 聚合酶 II（一种读取和解码 DNA 的蛋白质复合物）的流动，H3K4me3 决定基因表达何时开始以及它运行的速度。当信号灯处在“绿灯”状态时，H3K4me3 允许 RNA 聚合酶 II 沿着 DNA 移动并将其转录成 RNA。但若没有 H3K4me3，RNA 聚合酶 II 会卡在 DNA 的启动子近端区域，造成阻碍减慢转录。建立研究H3K4甲基化的模型H3K4的甲基化受SET1/COMPASS复合物的直接调控。SET1/COMPASS由多个赖氨酸甲基转移酶和若干个亚单位构成，因此各个蛋白构建存在功能冗余。而这也使确定 H3K4 甲基化在基因表达中的直接作用变得十分困难。为研究H3K4 甲基化在转录中的作用，研究人员开发了DPY30 或 RBBP5 的急性耗竭（acute depletion）模型系统。之所以选择DPY30 和 RBBP5是因为这两个核心成分是小鼠胚胎干 (mES) 细胞系中所有 SET1/COMPASS 复合物家族不可或缺的共享成分。为了构建急性耗竭模型，研究人员在mES 细胞中表达了DPY30 或RBBP5与degron（一种可促进蛋白降解的蛋白）的融合蛋白。其中DPY30与受生长素调控的mAID degron tag融合，RBBP5则与受dTAG-13调控的FKBP degron tag融合。用该细胞模型进行实验的结果表明，DPY30 或 RBBP5 的急性耗竭会导致 H3K4 甲基化的快速丧失。图注：靶向DPY30 或 RBBP5的 degron系统【1】去甲基化酶KDM5 调控 H3K4me3 的快速转化那么，H3K4me3 的快速丧失是受谁的调控呢？组蛋白转化和主动去甲基化是2个可能的机制。为了研究 H3K4me3 的快速转化是否是由于 KDM5 H3K4me3/me2 去甲基化酶的活性，研究人员敲除了 DPY30–mAID mES 细胞系中的Kdm5a和Kdm5b基因。他们发现与 DPY30-mAID 细胞相比， H3K4me3 在 Kdm5a/b敲除细胞（dKO）中持续存在时间显著延长，表明H3K4me3 的快速转化依赖于 mES 细胞中的去甲基化酶KDM5A 和 KDM5B。基因转录的调控需要H3K4me3为了研究H3K4me3 快速丧失后对转录的主要影响，研究人员使用 SLAM-seq 在 degron 细胞系中测量了新转录 RNA 的合成速率。用生长素处理 dKO 细胞和DPY30-mAID 细胞后进行的 SLAM-seq 分析发现，DPY30-mAID细胞下调的基因数量远多于dKO细胞，说明H3K4me3 是调节转录的决定性因素。图注：基因转录的调控需要H3K4me3【1】H3K4me3是如何调控转录的呢？研究人员发现H3K4me3 的快速丧失会促进RNA 聚合酶II 在启动子区域的暂停（RNAPII pausing）。他们进一步利用高分辨率的mNET-seq对dKO细胞和DPY30-mAID进行分析，发现与DPY30-mAID细胞相比，dKO细胞的RNAPII pausing存在显著延迟，表明H3K4me3参与调控RNA 聚合酶II的暂停与释放。图注：H3K4me3 的快速丧失延长 RNAPII pausing的停留时间【1】那么，H3K4me3通过RNA 聚合酶II的调控对基因转录产生了怎样的影响呢？研究人员利用TTchem-seq和mNET-seq技术测量的转录延伸速率，发现H3K4me3快速丧失会降低延伸速率。INTS11参与H3K4me3调控的启动子近端暂停-释放（promotor proximal pausing-release）研究人员接下来探究可能参与受H3K4me3调控的启动子近端暂停释放的蛋白质。他们利用ChIP-MS识别了3个蛋白并对其中的INTS11（一个核酸内切酶亚基）做后续研究。他们发现与H3K4me3相似，INTS11的快速丧失会促进RNA 聚合酶II的暂停。进一步显示H3K4me3 通过招募INTS11 的机制调节启动子近端暂停，这于RNAPII pausing的取消和转录延伸至关重要。图注：H3K4me3调控转录的机制【1】此项研究的负责人，表观遗传学研究专家、伦敦癌症研究所的首席执行官Kristian Helin教授表示：“我们的研究提供了对表观遗传学的新理解，这是一个非常令人兴奋但仍未充分探索的癌症领域研究。揭示了一种著名的表观遗传修饰如何控制基因表达，解决了一个存在 20 年的难题。由于决定细胞中 H3K4me3 水平的酶经常在癌症中发生突变，这项研究可能对理解和治疗癌症具有重要意义。”【2】参考文献：【1】 Wang, H., Fan, Z., Shliaha, P.V. et al. H3K4me3 regulates RNA polymerase II promoter-proximal pause-release. Nature (2023). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-023-05780-8【2】New study unveils epigenetic 'traffic lights' controlling stop and go for gene activity (2023, March 1) retrieved 3 March 2023 from https://medicalxpress.com/news/2023-03-unveilsepigenetic-traffic-gene.html撰文 | Qianyue编辑 | cici会议推荐RECOMMENDATIONS点击了解详情点击了解详情精彩推荐：1、改写现状！全球迄今最大规模细胞治疗心衰试验结果公布，心梗、中风发生率降低58%，可长期改善患者预后！2、“无肉不欢”是真的！近1.5万人研究表明：不吃肉，抑郁发作风险增加165%！3、我国已是“帕金森第一大国”！NEJM重磅研究：这种“无创疗法”可使70%帕金森患者显著改善症状！4、比免疫疗法更有效！Nature子刊：新型光激活抗癌疗法，有望成为实体瘤治疗利器！5、癌细胞真的能被饿死吗？《Nature》: 重磅！普林斯顿研究人员发现肿瘤代谢比预想的慢！

核酸药物基因疗法

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。