Mutations of Chromatin and its Modifying Machineries in Malignancies

恶性肿瘤中染色质及其修饰机制的突变

• 批准号: 10705758
• 负责人: Ali Shilatifard
• 金额: $ 92.74万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-13 至 2029-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705758
• 关键词: Aging; Biochemical; Biological Models; Cancer Etiology; Cataloging; Cells; Chicago; Chromatin; Chromatin Remodeling Factor; Clinic; Clinical; Clinical Trials; Collaborations; Complex; Dedications; Deubiquitinating Enzyme; Development; Developmental Gene Expression Regulation; Diffuse intrinsic pontine glioma; Endogenous Factors; Enhancers; Epigenetic Process; Equilibrium; Family; Funding; Gene Expression Profile; Gene Expression Regulation; Goals; Grant; H3 K27M mutation; Histones; Human; Laboratories; MLL gene; Malignant Neoplasms; Medicine; Molecular; Mutation; Outcome; Pathogenesis; Pathway interactions; Pediatric Hospitals; Positioning Attribute; Property; Proteins; Reagent; Regulation; Research; Role; Secure; Somatic Mutation; Structure; Testing; base; cancer therapy; improved; inhibitor; patient prognosis; targeted treatment; tool; ubiquitin isopeptidase

Project Summary Collective studies from my laboratory have focused on the molecular characterization of the function(s) and biochemical properties of the epigenetic modifiers and the mutations that are associated with human cancer. Our goal has been to determine how the mutations in these factors molecularly change the pattern of gene expression resulting in cellular hyperproliferation and use these molecular pathways to identify targeted therapeutics for cancer. Our detailed structural studies supported during the past seven years by this grant R35CA197569 have allowed us to identify the atomic structure of Set1/COMPASS, and based on this information, we have generated inhibitors towards its activity that are now being developed in our laboratory as a tool compound to regulate COMPASS's function in cells for the ultimate use in clinic. On other fronts, our analyses of the role of MLL3/COMPASS identified its interactions with the histone deubiquitinating enzyme BAP1, providing a central epigenetic balance at enhancers and the regulation of gene expression in cancer caused as the result of MLL3 mutations. Based on this information, we have a clinical trial at Northwestern Medicine investigating the epigenetic role of this balance in cancer therapy. We have also generated BAP1 inhibitors that can regulate hyperactivated BAP1 function in cancers caused as the result of ASXL1 mutations and such BAP1 inhibitors are being further investigated in our laboratory as biochemical and clinical tools. Our detailed analysis of the role of histone H3K27M mutations in diffuse intrinsic pontine gliomas (DIPG) resulted in the identification of a role for BET-domain containing factors such as Brd2 and Brd4 in DIPG pathogenesis. We are collaborating with colleagues at Lurie Children's Hospital of Chicago to test these findings in clinic. These studies also resulted in the identification of CATACOMB as an endogenous factor mimicking H3K27M and regulating PRC2 function. As will be described in the application, other studies in the laboratory have probed the mechanistic properties of diverse epigenetic factors in developmental regulation and in cancer. Additionally, recent cataloging of somatic mutations in cancer and during natural aging has identified a large number of mutations in the components of the MLL1-4, UTX, Set1A/B, and other epigenetic factors. Given that we have developed a fantastic set of reagents and tools over the past twenty years in our laboratory towards these factors, their associated proteins, chromatin, and other chromatin modifiers in multiple model systems, my laboratory is in a very unique and strong position to define the molecular bases of these factors’ involvement in cancer pathogenesis, and thus, for the purpose of targeted therapeutics. The goals of this R35 renewal application are the continuation of our full molecular and biochemical characterization of the trithorax COMPASS family and BAP1 complexes in the regulation of developmental gene expression, and how their mutations contribute to the pathogenesis of human cancer.

项目摘要 我实验室的集体研究集中于功能的分子表征和 表观遗传修饰剂的生化特性和与人类癌症相关的突变。 我们的目标是确定这些因素中的突变如何分子改变基因模式 表达导致细胞超增殖并使用这些分子途径鉴定靶向 癌症治疗剂。我们在过去七年中支持的详细结构研究由这笔赠款 R35CA197569使我们能够识别Set1/Compass的原子结构，并基于此 信息，我们已经对其活动产生了抑制剂，这些抑制剂现在正在我们的实验室中开发为 一种工具化合物，可调节指南针在细胞中的功能，以最终在临床中使用。在其他方面，我们的 MLL3/Compass的作用的分析确定了其与组蛋白去泛素化酶的相互作用 BAP1，在增强子方面提供中央表观遗传平衡，并调节癌症的基因表达 导致MLL3突变引起。根据这些信息，我们在西北地区进行了临床试验 研究这种平衡在癌症治疗中的表观遗传作用的医学。我们还产生了BAP1 可以调节ASXL1突变引起的癌症中过度活化BAP1功能的抑制剂 这种BAP1抑制剂正在我们的实验室进一步研究为生化和临床工具。我们的 组蛋白H3K27M突变在弥漫性内在蓬托胶质瘤（DIPG）中的作用的详细分析导致 在DIPG发病机理中鉴定包含Bet域的作用，例如BRD2和BRD4。我们 正在与芝加哥Lurie儿童医院的同事合作，在诊所测试这些发现。这些 研究还导致了迪马白症作为模拟H3K27M和的内源性因子的鉴定。 调节PRC2功能。正如应用程序中所述，实验室中的其他研究证明了 潜水员表观遗传因子在发育调节和癌症中的机械性能。此外， 最近在癌症和自然衰老期间对体细胞突变的分类已经确定了大量 MLL1-4，UTX，SET1A/B和其他表观遗传因素的组件中的突变。鉴于我们有 在过去的二十年中，在我们的实验室中开发了一套奇妙的试剂和工具，用于这些因素， 它们相关的蛋白质，染色质和其他染色质修饰剂在多种模型系统中，我的实验室是 在非常独特且强大的位置来定义这些因素参与癌症的分子碱基 发病机理，因此出于靶向治疗的目的。 R35续订应用的目标 是我们的完整分子和生化特征的延续 在调节发展基因表达的调节中的家庭和BAP1复合物及其如何 突变有助于人类癌的发病机理。

项目成果

Inhibition of DNA methyltransferases and histone deacetylases induces astrocytic differentiation of neural progenitors.

• DOI: 10.1016/j.scr.2013.03.003
• 发表时间: 2013-07
• 期刊: Stem cell research
• 影响因子: 1.2
• 作者: A. Majumder;S. Dhara;R. Swetenburg;M. Mithani;Kaixiang Cao;M. Medrzycki;Yuhong Fan;S. Stice

Drosophila TDP-43 RNA-Binding Protein Facilitates Association of Sister Chromatid Cohesion Proteins with Genes, Enhancers and Polycomb Response Elements.

• DOI: 10.1371/journal.pgen.1006331
• 发表时间: 2016-09
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Swain A;Misulovin Z;Pherson M;Gause M;Mihindukulasuriya K;Rickels RA;Shilatifard A;Dorsett D
• 通讯作者: Dorsett D

A small UTX stabilization domain of Trr is conserved within mammalian MLL3-4/COMPASS and is sufficient to rescue loss of viability in null animals.

• DOI: 10.1101/gad.339762.120
• 发表时间: 2020-11-01
• 期刊: Genes & development
• 影响因子: 10.5
• 作者: Rickels R;Wang L;Iwanaszko M;Ozark PA;Morgan MA;Piunti A;Khalatyan N;Soliman SHA;Rendleman EJ;Savas JN;Smith ER;Shilatifard A
• 通讯作者: Shilatifard A

An Mll4/COMPASS-Lsd1 epigenetic axis governs enhancer function and pluripotency transition in embryonic stem cells.

• DOI: 10.1126/sciadv.aap8747
• 发表时间: 2018-01
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Cao K;Collings CK;Morgan MA;Marshall SA;Rendleman EJ;Ozark PA;Smith ER;Shilatifard A
• 通讯作者: Shilatifard A

An Evolutionary Conserved Epigenetic Mark of Polycomb Response Elements Implemented by Trx/MLL/COMPASS.

• DOI: 10.1016/j.molcel.2016.06.018
• 发表时间: 2016-07-21
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Rickels R;Hu D;Collings CK;Woodfin AR;Piunti A;Mohan M;Herz HM;Kvon E;Shilatifard A
• 通讯作者: Shilatifard A