Defining transcriptional networks and chromatin conformations regulating glioma tumorigenesis

定义调节神经胶质瘤发生的转录网络和染色质构象

基本信息

批准号：
10593957
负责人：
Stacey Marie Glasgow
金额：
$ 39.5万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593957
关键词：
Address Adult Architecture Astrocytes Biochemical Biological Assay Biology Cell Differentiation process Cell Fate Control Central Nervous System Chick Chromatin Chromatin Loop Complex Coupled DNA DNA Binding DNA Sequence Alteration Data Development Diagnosis Disease Electroporation Embryo Enhancers Gene Expression Gene Expression Regulation Gene Targeting Generations Genes Genetic Transcription Genomic Instability Glioma Gliomagenesis Hi-C Human In Vitro Lead Link Malignant - descriptor Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Mediating Mediator Modeling Molecular Conformation Molecular Target Mus NF1 gene NFIA gene Neuroglia Neurons Nuclear Oncogenes PTEN gene Pathologic Pathway interactions Patients Peptide Initiation Factors Population Primary Brain Neoplasms Prognosis Progression-Free Survivals Proteins Regulator Genes Regulatory Element Role Structure Survival Rate System TP53 gene Techniques Technology Therapeutic Tissue Microarray Tumor Cell Biology Work chromosome conformation capture driver mutation effective therapy embryonic stem cell gain of function gene function genome-wide analysis glial cell development gliogenesis glioma cell line in utero in vitro Assay in vivo insight loss of function mRNA Expression mouse genetics mouse model nerve stem cell novel programs promoter protein expression stem cells transcription factor tumor tumorigenesis

项目摘要

Malignant gliomas are the most common and deadly primary brain tumor. Despite current therapeutic approaches, most glioma patients die within one year of diagnosis. Genomic instability coupled with aberrant regulation of cell-fate decisions in progenitor cell populations has been linked to glioma, leading to the view that a convergence of genetic mutation and developmental context lead to tumorigenesis. Recent findings demonstrate that a large set of developmental transcription factors are activated in gliomas. These studies suggest that the gene regulatory programs governing glial cell formation are reutilized during glioma formation, pointing to common transcriptional requirements for glial development and tumorigenesis. Therefore, it is critical that we leverage our understanding of glial cell development to gain valuable insights into the biology and treatment of gliomas. We have previously identified a gliogenic transcriptional complex – Sox9/Brn2– that is important for the initiation of gliogenesis. We showed that in a mouse model of malignant glioma disruption of the ability of the complex to bind DNA regulatory elements leads to decreased expression of the glial initiating factor Nuclear Factor-IA (NFIA) and reduced tumorigenesis. Our preliminary data demonstrate that a protein Med12 (Mediator Complex subunit 12), which is expressed during glial cell development, linked to chromatin conformations, and implicated in cancer tumorigenesis, associates with the Sox9/Brn2 complex. Further, reduction of Med12 expression in cortical astrocyte cultures compromises DNA chromatin conformation at the Nfia locus. Therefore, we propose to explore the parallels between embryonic glial development and tumorigenesis by delineating the transcriptional circuitry and regulatory landscape governing glioma tumorigenesis. Analysis of these mechanisms is expected to identify molecular targets important in gliomagenesis. We focus this proposal on the function of a transcriptional complex, important for glial cell differentiation, -Sox9/Brn2/Med12- and its role in coordinating transcriptional mechanisms through gene regulatory elements, and chromatin conformations during gliomagenesis. We will investigate the role of Med12 in glioma formation and tumor cell biology using a wide range of in vitro and in vivo techniques in a novel mouse model of malignant glioma. We will interrogate the mechanisms by which Med12 functions in mediating enhancer/promoter interaction during glioma formation and progression by exploiting recent technological advances that allow for examination of long-range chromatin interactions (i.e. 3C Assays). We will functionally validate downstream target genes of the Sox9/Brn2/Med12 complex that may influence glioma formation. Together, these studies will define how developmentally relevant transcriptional mechanisms including gene regulatory elements and chromatin architecture interface to influence glioma biology and reveal novel gene targets potentially regulating gliomagenesis.

恶性神经胶质瘤是最常见和致命的原发性脑肿瘤。尽管目前的疗法接近，大多数神经胶质瘤患者在诊断后一年内死亡。基因组不稳定性和异常祖细胞群体中细胞命运决策的调节与神经胶质瘤有关，导致认为遗传突变和发育环境的收敛导致肿瘤发生。最新发现证明在神经胶质瘤中激活了大量的发育转录因子。这些研究表明在神经胶质瘤形成期间，控制神经胶质细胞形成的基因调节程序被重新注射，指出神经胶质发育和肿瘤发生的常见转录要求。因此，这很关键我们利用对神经胶质细胞开发的理解来获得对生物学的宝贵见解和神经胶质瘤的治疗。我们以前已经确定了神经胶质转录复合物 - Sox9/brn2- 对于神经胶质发生的主动性很重要。我们表明，在一种恶性神经胶质瘤破坏的小鼠模型中复合物结合DNA调节元件的能力导致胶质神经胶质的表达降低因子核因子-IA（NFIA）和肿瘤发生减少。我们的初步数据表明蛋白质在神经胶质细胞发育过程中表达的Med12（介体复合体亚基12）与染色质有关构象并在癌症肿瘤发生中实施，与SOX9/BRN2复合物相关联。更远，皮质星形胶质细胞培养物中Med12表达的降低会损害DNA染色质构象 NFIA基因座。因此，我们建议探索胚胎神经胶质发育与肿瘤发生通过描述转录电路和控制神经胶质瘤的调节景观肿瘤发生。对这些机制的分析有望确定在神经胶质作用。我们将此建议重点放在转录复合物的功能上，对于神经胶质细胞分化很重要， -sox9/brn2/med12-及其在基因调节元件的协调转录机制中的作用，和神经胶质作用过程中的染色质构象。我们将研究Med12在神经胶质瘤形成中的作用在新型的恶性小鼠模型中，使用多种体外和体内技术使用肿瘤细胞生物学神经胶质瘤。我们将询问MED12在介导增强子/启动子中功能的机制胶质瘤形成期间的相互作用和进展，通过利用最近的技术进步检查远程染色质相互作用（即3C分析）。我们将在下游功能验证可能影响神经胶质瘤形成的SOX9/BRN2/MED12复合物的靶基因。这些研究将在一起定义如何开发相关的转录机制，包括基因调节元件和染色质结构界面影响神经胶质瘤生物学并揭示了潜在调节的新基因靶标神经胶质作用。