Defining the Function of Age-Related Epimutation in Intestinal Tumorigenesis

定义年龄相关表突变在肠道肿瘤发生中的功能

基本信息

批准号：
10460369
负责人：
Lanlan Shen
金额：
$ 35.09万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-08 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10460369
关键词：
APC mutation Aberrant DNA Methylation Aging ApcMin/+ mice Applications Grants BRAF gene Binding Binding Proteins Biological Biological Assay Biological Models CCAAT-Enhancer-Binding Protein-alpha CDKN2A gene Cancer Biology Cancer Etiology Carcinoma Catalogs Cell Aging Cell Cycle Regulation Cell physiology Cessation of life ChIP-seq Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Colon Carcinoma Colorectal Cancer Communities Complex CpG Islands Cyclin-Dependent Kinase Inhibitor 2A Cytosine DNA DNA Methylation DNA Sequence Alteration DNA-Binding Proteins Data Defect Development Engineering Epigenetic Process Etiology Event Fluorouracil Gene Expression Gene Silencing Genes Goals Heritability Human Hypermethylation Immunocompetent In Vitro Intervention Intestinal Cancer Intestinal Neoplasms KDM1A gene Laboratories Lentivirus Vector MAP Kinase Gene Maintenance Malignant - descriptor Malignant Neoplasms Mediating Methylation Mitotic Modeling Molecular Monitor Mus Mutation NuRD complex Oncogenic Organoids Pathogenesis Pathogenicity Pathway interactions Patients Pattern Phenotype Prevention Proteins Public Health Publishing Ras/Raf Reader Research Robin bird Role Stress System Testing Therapeutic Intervention Tissues Tumor Suppressor Genes WNT Signaling Pathway Work adenoma age related anticancer research base beta catenin bisulfite sequencing cancer cell cancer initiation cancer prevention cancer therapy carcinogenesis chemotherapy clinical care colon cancer patients colon tumorigenesis demethylation design epigenetic regulation epigenetic silencing epigenetic therapy epigenomics experimental study gene function genome-wide improved in vivo in vivo Model intestinal tumorigenesis mouse model new therapeutic target novel organoid transplantation promoter recruit response targeted treatment transcription factor transcriptome sequencing treatment response tumor tumor growth tumor progression tumorigenic

项目摘要

PROJECT SUMMARY Epimutation – mitotically stable gene silencing associated with epigenetic alteration in DNA methylation – is now recognized as a common feature of human cancer. Indeed, recent epigenomic studies revealed that nearly all tumor types harbor hundreds of aberrantly hypermethylated and silenced promoter CpG island- associated (CGI-associated) genes, highlighting the need to identify driver epimutations. In this regard, we developed a novel mouse model of epimutation in a tumor suppressor gene p16 (also known as cyclin- dependent kinase inhibitor 2A). We found that engineered promoter methylation leads to accelerated p16 epimutation in mouse somatic tissues during aging. We demonstrated that p16 epimutation predisposes mice to spontaneous tumor development. In addition, our preliminary work shown that p16 epimutation can cooperate with mutational Apc to accelerate intestinal tumorigenesis using the ApcMin/+ mice. Importantly, we found that p16 epimutation functions beyond the classically known cell-cycle control to induce malignant transformation of intestinal neoplasms. Therefore, based on our strong preliminary data, we hypothesize that p16 epimutation, commonly observed in human sporadic CRCs as part of the age-related epigenetic alteration, cooperates with genetic alterations to drive intestinal cancer initiation and progression. We will test this by 1) Determine how p16 epimutation promotes intestinal tumorigenesis. We will assess the biological consequences of p16 epimutation through its interactions with two key signaling pathways: WNT-APC-β- catenin and MAPK-RAS-RAF; 2) Determine whether reversal of epigenetic defects in p16 suppresses tumor growth. We will evaluate tumor responses to the reversal of p16 epimutation by applying a CRISPR-based targeted p16 promoter demethylation; and 3) Determine whether transcription factors as a reader of methylated DNA mediate the function of p16 epimutation. We will investigate the molecular events by which p16 epigenetic silencing is a result from DNA methylation dependent trans-acting protein binding which subsequently recruits chromatin repressive complexes. These studies will elucidate how aberrant DNA methylation, an important epigenetic mechanism regulating the expression of tumor suppressor genes, drives colorectal tumorigenesis. The results derived from this proposal could have a unique impact in the design of colon cancer epigenetic therapies.

项目概要表观突变——与 DNA 甲基化表观遗传改变相关的有丝分裂稳定基因沉默——是事实上，最近的表观基因组研究表明，现在已被认为是人类癌症的一个共同特征。几乎所有肿瘤类型都含有数百个异常高甲基化和沉默的启动子 CpG 岛 - 相关（CGI 相关）基因，强调需要识别驱动表观突变。在这方面，我们。开发了一种新型小鼠肿瘤抑制基因 p16（也称为细胞周期蛋白）表突变模型。依赖性激酶抑制剂 2A)。我们发现工程启动子甲基化导致 p16 加速。衰老过程中小鼠体组织的表突变我们证明p16表突变使小鼠易感。此外，我们的初步工作表明p16表突变可以影响肿瘤的自发发展。重要的是，我们使用 ApcMin/+ 小鼠与突变 Apc 合作加速肠道肿瘤发生。发现 p16 表突变功能超出了经典已知的细胞周期控制，可诱导恶性因此，根据我们强有力的初步数据，我们发现了这一点。 p16 表观突变，通常在人类散发的 CRC 中观察到，作为与年龄相关的表观遗传改变的一部分，与基因改变合作驱动肠癌的发生和进展，我们将通过 1) 来测试这一点。确定 p16 表突变如何促进肠道肿瘤发生我们将评估其生物学特性。 p16 表观突变通过与两个关键信号通路相互作用产生的后果：WNT-APC-β- 连环蛋白和 MAPK-RAS-RAF；2) 确定 p16 表观遗传缺陷的逆转是否会抑制肿瘤我们将通过应用基于 CRISPR 的方法来评估肿瘤对 p16 表观突变逆转的反应。靶向 p16 启动子去甲基化；和 3) 确定转录因子是否作为阅读器甲基化 DNA 介导 p16 表突变的功能我们将研究其分子事件。 p16 表观遗传沉默是 DNA 甲基化依赖性反式作用蛋白结合的结果，随后招募染色质抑制复合物，这些研究将阐明异常 DNA 是如何发生的。甲基化是调节抑癌基因表达的重要表观遗传机制，驱动该提案得出的结果可能对结直肠肿瘤的设计产生独特的影响。结肠癌表观遗传疗法。