Role of gene enhancer elements in colon cancer

基因增强子元件在结肠癌中的作用

基本信息

批准号：
8633432
负责人：
SANFORD D. MARKOWITZ
金额：
$ 39.48万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8633432
关键词：
Accounting Adult American Back Binding Biological Assay Biological Process Cancer Etiology Cancer Patient Cell Line Cells Cessation of life ChIP-seq Chromosomes Clinical Colon Colon Carcinoma Colonic Neoplasms Colorectal Neoplasms DNA DNA Sequence Data Derivation procedure Disease Disease Progression Distal Embryo Enhancers Epigenetic Process Epithelium Event Fibroblasts Frequencies Functional RNA Gene Expression Gene Mutation Genes Genetic Genetic Enhancer Element Genome Genomics Goals Histone H3 Human Hybrids Indium Knock-in Mouse Learning Location Luciferases Lysine Malignant Neoplasms Maps Mediating Memory Methods Modeling Molecular Conformation Mono-S Mutation Neoplasm Metastasis Phenotype Process Relative (related person)Reporter Role Sampling Signal Transduction Somatic Cell Somatic Mutation Staging Technology Testing Therapeutic Studies Tumor-Derived Variant cancer cell carcinogenesis cohort colon cancer cell line genome-wide induced pluripotent stem cell innovation insight intestinal epithelium mortality novel research study restoration transcription factor tumor tumor progression vector

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this proposal is to identify genetic and epigenetic alterations occurring at gene enhancer elements in colon cancer, and to gain insights into how these events mediate disease progression. Cancer is due to the progressive accumulation of mutations in DNA, as well as heritable changes in gene expression caused by mechanisms other than mutations in the underlying DNA sequence, so called epigenetic alterations. Gene enhancer elements are short regions of DNA to which transcription factors bind in order to increase the expression of a gene. Enhancers are almost certainly altered at both the genetic and epigenetic level in cancer, although the extent by which this occurs is unknown. Using state of the art ChIP-seq technology, we identified the locations of gene enhancer elements across the entire genome in cells derived from human colon cancer and normal colon. While the locations of many enhancers remain unchanged, thousands of enhancer loci differ between normal colon and colon cancer cells. We call these regions variations at enhancer loci, or VELs. We hypothesize that VELs, which either contain somatic mutations or are purely epigenetically derived, contribute to the formation and progression of colon tumors. Three specific aims are proposed. In Aim 1 we will systematically assess the relationship between VELs and colon cancer progression through characterization of VELs in a cohort of well-characterized primary cell lines that comprehensively capture all of the clinical stages of colon cancer. In Aim 2, we will conduct DNA sequencing of VELs in tumor and matched normal DNA from ten colon cancer patients to identify somatic mutations that may have accrued at gene enhancer elements during carcinogenesis. In Aim 3, we will assess the plasticity and reversibility of the VELs through innovative experiments in which colon cancer cells are reverted to the embryonic state and then re- differentiated into colon epithelium. The successful completion of these Aims will accelerate our understanding of epigenetics and the role of a class of non-coding functional elements in colon cancer, which could ultimately have important implications for therapeutic studies aimed at targeting restoration of aberrantly expressed genes in colon cancer.

描述（由申请人提供）：该提案的总体目标是识别结肠癌基因增强子元件处发生的遗传和表观遗传改变，并深入了解这些事件如何介导疾病进展。癌症是由于 DNA 突变的逐渐积累以及由基础 DNA 序列突变以外的机制引起的基因表达的遗传性变化（所谓的表观遗传改变）造成的。基因增强子元件是 DNA 的短区域，转录因子与其结合以增加基因的表达。几乎可以肯定，增强子在癌症的遗传和表观遗传水平上都发生了改变，尽管这种改变发生的程度尚不清楚。利用最先进的 ChIP-seq 技术，我们确定了源自人类结肠癌和正常结肠的细胞中基因增强子元件在整个基因组中的位置。虽然许多增强子的位置保持不变，但正常结肠和结肠癌细胞之间有数千个增强子位点不同。我们将这些区域称为增强子基因座变异（VEL）。我们假设含有体细胞突变或纯粹表观遗传衍生的 VEL 有助于结肠肿瘤的形成和进展。提出了三个具体目标。在目标 1 中，我们将通过在一组全面捕获结肠癌所有临床阶段的充分表征的原代细胞系中对 VEL 进行表征，系统地评估 VEL 与结肠癌进展之间的关系。在目标 2 中，我们将对肿瘤中的 VEL 和来自 10 名结肠癌患者的匹配正常 DNA 进行 DNA 测序，以识别在癌发生过程中基因增强子元件可能产生的体细胞突变。在目标 3 中，我们将通过创新实验评估 VEL 的可塑性和可逆性，其中结肠癌细胞恢复到胚胎状态，然后重新分化为结肠上皮。这些目标的成功完成将加速我们对表观遗传学和一类非编码功能元件在结肠癌中的作用的理解，这最终可能对旨在恢复结肠癌中异常表达基因的治疗研究产生重要影响。