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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要我实验室的集体研究集中在功能和功能的分子表征上表观遗传修饰剂的生化特性以及与人类癌症相关的突变。我们的目标是确定这些因素的突变如何在分子上改变基因模式表达导致细胞过度增殖，并使用这些分子途径来识别目标过去七年里我们的详细结构研究得到了这笔资助的支持。 R35CA197569 使我们能够识别 Set1/COMPASS 的原子结构，并基于此信息，我们已经产生了针对其活性的抑制剂，目前我们的实验室正在开发这些抑制剂一种调节 COMPASS 在细胞中的功能的工具化合物，最终用于临床。 MLL3/COMPASS 的作用分析确定了其与组蛋白去泛素化酶的相互作用 BAP1，在增强子和癌症基因表达调控中提供中心表观遗传平衡基于此信息，我们在西北大学进行了一项临床试验。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生成了 BAP1。可以调节 ASXL1 突变引起的癌症中过度激活的 BAP1 功能的抑制剂我们的实验室正在进一步研究此类 BAP1 抑制剂作为生化和临床工具。对组蛋白 H3K27M 突变在弥漫性内源性脑桥胶质瘤 (DIPG) 中的作用进行了详细分析，得出鉴定了包含 BET 结构域的因子（例如 Brd2 和 Brd4）在 DIPG 发病机制中的作用。正在与芝加哥卢里儿童医院合作，在临床上测试这些发现。研究还发现 CATACOMB 是一种模仿 H3K27M 的内源性因子，正如申请中将描述的，实验室的其他研究已经探索了调节 PRC2 功能。发育调节和癌症中多种表观遗传因素的机制特性。最近对癌症和自然衰老过程中的体细胞突变进行了分类，发现了大量 MLL1-4、UTX、Set1A/B 和其他表观遗传因子的成分发生突变。在过去的二十年里，我们的实验室针对这些因素开发了一套出色的试剂和工具，它们的相关蛋白质、染色质和其他染色质修饰剂在多个模型系统中的研究，我的实验室是在定义这些因素参与癌症的分子基础方面处于非常独特和强有力的地位发病机制，从而达到靶向治疗的目的。R35更新应用的目标。是我们对 Trithorax COMPASS 完整分子和生化特征的延续家族和 BAP1 复合物在发育基因表达调控中的作用，以及它们如何突变有助于人类癌症的发病机制。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
通讯作者：
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