Chromatin Modifications in GBM-Propagating Cells

GBM 增殖细胞中的染色质修饰

基本信息

批准号：
9886285
负责人：
John J Laterra
金额：
$ 47.08万
依托单位：
HUGO W. MOSER RES INST KENNEDY KRIEGER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9886285
关键词：
Animals Architecture Automobile Driving Binding Cells Chromatin Chromatin Structure Code Complement DNA Binding DNA-Binding Proteins Development Epigenetic Process Event Foundations Gene Expression Generations Genetic Transcription Glioblastoma Glioma Goals Growth HMGA1 gene Histones Maintenance Malignant Neoplasms Malignant neoplasm of brain Maps MicroRNAs Molecular Oncogenes Patients Pharmacology Phenotype Play Polycomb Population Primary Brain Neoplasms Proteins Recurrence Regulation Repression Repressor Proteins Research Role Structure Structure-Activity Relationship Therapeutic Transcriptional Regulation Treatment Efficacy Untranslated RNA Up-Regulation Xenograft procedure base chromatin modification combinatorial design effective therapy genome-wide improved in vivo inhibitor/antagonist innovation nanoparticle new therapeutic target novel novel strategies novel therapeutics programs reconstitution relating to nervous system response stem stem cells stem-like cell stemness therapeutic development therapeutic evaluation therapy resistant transcription factor transcriptome treatment strategy tumor tumor growth

项目摘要

SUMMARY/ABSTRACT Glioblastoma multiforme (GBM), the most common brain cancer, is universally fatal with median survival of ~ 18 months. New therapies are desperately needed. GBM is heterogeneous at the cellular level with small populations of tumor propagating stem-like cells (aka, GBM stem cells, GSCs) that contribute disproportionately to GBM growth, therapeutic resistance and recurrence. Substantial evidence indicates that GBM cells are highly plastic and dynamically transition between the stem-like/tumor propagating phenotype and more differentiated/non-tumor propagating phenotype in response to contextual epigenetic events. Elucidating the epigenetic mechanisms involved in the generation and maintenance of GSCs (i.e. repression of differentiating and activation of dedifferentiation transcriptional programs) is critical to understanding the molecular underpinnings of glioblastoma malignancy and will further the development of more effective therapeutics. We have found that the reprogramming transcription factors Oct4 and Sox2 (Oct4/Sox2) phenotypically reprogram non-GSCs to tumor-propagating GSCs through the silencing of miRNAs that cooperatively inhibit the GSC phenotype. We now hypothesize that the repression of specific miRNAs that target (i) the non-histone DNA-binding protein HMGA1, and (ii) components of the polycomb repressor complex 2 (PRC2) that catalyzes histone3K27 trimethylation (H3K27me3) plays an essential role in the generation of GSCs by Oct4/Sox2. This proposal focuses on how HMGA1 and PRC2 cooperatively regulate chromatin structure and function and gene expression during the induction of tumor propagating GSCs by Oct4/Sox2 and on testing the therapeutic efficacy of inhibiting these Oct4/Sox2-regulated miRNA circuits. These goals will be achieved via three specific aims- (1) Determine the role of Oct4/Sox2-repressed miRNAs in the up-regulation of HMGA1, PRC2, H3K27me3 and GSC induction by Oct4/Sox2; (2) Determine how HMGA1 and H3K27me3 co-regulate chromatin function and transcriptional networks in response to Oct4/Sox2; (3) Develop novel GBM treatment strategies based on inhibiting these mechanism of GSC induction by Oct4/Sox2. This research will fill critical gaps in our understanding of how reprogramming transcriptions factors induce GSCs and GBM propagation. We will specifically identify how the “structural transcription factor” HMGA1 and the PRC2-dependent H3K27me3 cooperate to regulate the GSC-inducing transcriptome. We will also evaluate the potential to therapeutically target these novel GSC-drivers using innovative nanoparticle- based and pharmacologic therapeutics.

摘要/摘要多形性胶质母细胞瘤 (GBM) 是最常见的脑癌，普遍致命，中位生存期约为 ~ 18 个月，迫切需要新的治疗方法，GBM 在细胞水平上具有异质性。肿瘤增殖干细胞（又名 GBM 干细胞，GSC）群体大量证据表明，与 GBM 生长、治疗耐药和复发不成比例。 GBM 细胞具有高度可塑性，并且在干细胞样/肿瘤增殖表型之间动态转变以及响应背景表观遗传事件的更多分化/非肿瘤传播表型。阐明参与 GSC 生成和维持的表观遗传机制（即抑制去分化转录程序的分化和激活）对于理解胶质母细胞瘤恶性肿瘤的分子基础，并将进一步开发更有效的我们发现重编程转录因子 Oct4 和 Sox2 (Oct4/Sox2) 通过沉默 miRNA，将非 GSCs 表型重编程为肿瘤增殖性 GSCs 我们现在捕获了特定 miRNA 的抑制作用。目标 (i) 非组蛋白 DNA 结合蛋白 HMGA1，以及 (ii) 多梳阻遏蛋白的成分催化组蛋白 3K27 三甲基化 (H3K27me3) 的复合物 2 (PRC2) 在 Oct4/Sox2 生成 GSC 该提案重点关注 HMGA1 和 PRC2 如何合作调节。诱导肿瘤增殖 GSC 过程中的染色质结构和功能以及基因表达 Oct4/Sox2 并测试抑制这些 Oct4/Sox2 调节的 miRNA 回路的治疗效果。这些目标将通过三个具体目标来实现 - (1) 确定 Oct4/Sox2 抑制的 miRNA 在 Oct4/Sox2 对 HMGA1、PRC2、H3K27me3 和 GSC 诱导的上调 (2) 确定 HMGA1 的作用；和 H3K27me3 响应 Oct4/Sox2 共同调节染色质功能和转录网络 (3) 基于抑制 GSC 诱导的这些机制，开发新的 GBM 治疗策略 Oct4/Sox2。这项研究将填补我们对重编程转录因子如何理解的关键空白。我们将具体确定“结构转录因子”如何诱导 GSC 和 GBM 增殖。 HMGA1 和 PRC2 依赖性 H3K27me3 合作调节 GSC 诱导转录组。还评估了使用创新纳米颗粒治疗靶向这些新型 GSC 驱动因素的潜力基础和药物治疗。