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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：
10676178
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/10676178
关键词：
APC mutation Aberrant DNA Methylation Acceleration Aging ApcMin/+ mice Applications Grants BRAF gene Binding Binding Proteins Biological Biological Assay Biological Models CCAAT-Enhancer-Binding Proteins 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 Colon Carcinoma Colorectal Cancer Communities Complex CpG Islands Cyclin-Dependent Kinase Inhibitor 2A 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 Signal Pathway Stress System Testing Therapeutic Intervention Tissues Tumor Suppressor Genes Work adenoma age related anticancer research 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 initiation 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.

项目总结与DNA甲基化的表观遗传学改变相关的有丝分裂稳定的基因沉默现在被认为是人类癌症的共同特征。事实上，最近的表观基因组学研究表明几乎所有的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，突出了识别司机表型突变的必要性。在这方面，我们开发了一种新的肿瘤抑制基因p16(也称为细胞周期蛋白)突变的小鼠模型。依赖的激酶抑制物2A)。我们发现，基因工程的启动子甲基化导致p16基因加速衰老过程中小鼠体组织的突变。我们证明了p16基因突变使小鼠易患上到自发的肿瘤发展。此外，我们的初步工作表明，p16突变体可以利用ApcMin/+小鼠协同突变的APC加速肠道肿瘤的形成。重要的是，我们发现p16突变的功能超出了经典已知的细胞周期控制，可以诱导肿瘤发生肠道肿瘤的转化。因此，根据我们强劲的初步数据，我们假设 P16突变，通常在人类散发性癌中观察到，是年龄相关表观遗传学改变的一部分。与基因改变合作，推动肠癌的发生和发展。我们将对此进行测试1) 确定p16突变如何促进肠道肿瘤的发生。我们将评估生物 P16突变与WNT-APC-β两条关键信号通路相互作用的后果连环蛋白和MAPK-RAS-RAF；2)决定p16表观遗传缺陷的逆转是否抑制肿瘤成长。我们将通过应用基于CRISPR的方法来评估肿瘤对p16突变逆转的反应。靶向p16启动子去甲基化；以及3)确定转录因子是否作为阅读器 DNA甲基化介导了p16基因突变的功能。我们将研究分子事件， P16表观遗传沉默是DNA甲基化依赖的反式作用蛋白结合的结果随后招募染色质抑制复合体。这些研究将阐明异常的DNA是如何甲基化，一种重要的表观遗传机制，调节肿瘤抑制基因的表达结直肠肿瘤的发生。从这项建议中得出的结果可能会对设计产生独特的影响结肠癌的表观遗传疗法。