Transcriptional Mechanisms of Tumor Suppression

肿瘤抑制的转录机制

基本信息

批准号：
9044741
负责人：
MICHAEL P. VERZI
金额：
$ 35.46万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9044741
关键词：
Animal Model Benign Binding Biological Assay CDX2 gene Cells ChIP-seq Chromatin Chromatin Structure Clinical Colon Colon Carcinoma Colonic Neoplasms Colonic Polyps Colorectal Cancer Colorectal Neoplasms DNA Sequence Alteration Development Developmental Gene Diagnosis Diagnostic Neoplasm Staging Disease Enhancers Environment Epithelium Event Gene Expression Gene Expression Regulation Genes Genetic Genetic Epistasis Genome Genomic Segment Goals Growth Health Intestines Knock-out MADH4 gene Malignant Neoplasms Modeling Mutant Strains Mice Mutate Mutation Neoplasm Metastasis Oncogenic Pathway interactions Patients Phenotype Property Public Health Regulation Research Role Signal Transduction System TCF7L2 gene Testing Tissue Differentiation Tissues Transcriptional Regulation Tumor Suppression Tumor Suppressor Proteins Tumor Tissue WNT Signaling Pathway Work adenoma base epigenomics frontier genome-wide histone modification in vivo innovation malignant state mouse model novel outcome forecast prevent research study systems research temporal measurement transcription factor transcription factor CDX2 tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): After decades of outstanding research, the discovery of common genetic mutations occurring in colorectal cancer is nearing saturation. The next frontier will focus on identifying mechanisms downstream of these mutations that result in cancer progression. This proposal's main objective is to describe the transcriptional regulatory mechanisms by which the transcription factors CDX2 and SMAD4 suppress colon tumor progression. The central hypothesis is that these transcription factors stabilize tumors by maintaining chromatin structure and transcription factor regulatory networks that occur in normal, differentiated tissue. The rationale supporting this hypothesis is that 1) CDX2 and SMAD4 each function in development to establish the normal colon epithelium; and 2) that CDX2 and SMAD4 are each silenced or mutated during colon tumor progression. Aim 1 of the proposed work will take advantage of new mouse models to inactivate CDX2 in early and late cancer conditions to identify whether CDX2's transcriptional regulatory targets or control of chromatin structure are compromised in a way to support cancer growth. Preliminary evidence demonstrates CDX2-inactivation does indeed exacerbate the phenotype of a common oncogenic mouse model and that enhancer chromatin is altered when CDX2 is inactivated. Aim 2 will focus on elucidating the function of SMAD4 in colonic polyps. SMAD4 is one of the most frequently mutated genes in colon cancer but its transcriptional regulatory mechanisms in adenomas are unclear. A novel mouse model will be employed to inactivate SMAD4 in colonic polyps and immediately determine the consequences of SMAD4 loss on gene regulation and tumor chromatin structure. Finally, despite having similar functions in promoting tumor suppression and tissue differentiation, cooperativity between CDX2 and SMAD4 has not been investigated. Aim 3 will use a new mutant mouse to test for a genetic interaction between CDX2 and SMAD4 in the colon and potentially reveal a novel mechanism of tumor suppression. Existing research systems are unable to study the direct consequence of CDX2 or SMAD4 loss on tumor chromatin regulation in vivo. This approach is innovative in that we have assembled multiple animal models of colorectal cancer in which transcription factor knockout can be induced with precise temporal resolution. This system thus enables detailed genome-scale experiments to interrogate tumor transcriptional regulation. The proposed research is significant in that it is expected to identify a direct connection between tumor suppressing transcription factors, regulation of tumor chromatin structure, and novel mechanisms of transcriptional regulation of tumor progression.

描述（由申请人提供）：经过数十年的杰出研究，结直肠癌中常见基因突变的发现已接近饱和，下一个前沿将集中于识别导致癌症进展的这些突变的下游机制。描述转录因子 CDX2 和 SMAD4 抑制结肠肿瘤进展的转录调控机制，中心假设是这些转录因子通过维持正常分化组织中的染色质结构和转录因子调控网络来稳定肿瘤。支持这一假设的基本原理是：1) CDX2 和 SMAD4 各自在发育过程中发挥作用以建立正常结肠上皮；2) CDX2 和 SMAD4 在结肠肿瘤进展过程中各自被沉默或突变。新的小鼠模型在早期和晚期癌症条件下使 CDX2 失活，以初步确定 CDX2 的转录调控目标或染色质结构的控制是否受到损害以支持癌症生长。有证据表明 CDX2 失活确实会加剧常见致癌小鼠模型的表型，并且当 CDX2 失活时增强子染色质会发生改变，目标 2 将重点阐明 SMAD4 在结肠息肉中的功能，SMAD4 是最常见的突变基因之一。其在结肠癌中的作用，但其在腺瘤中的转录调控机制尚不清楚，我们将采用一种新的小鼠模型来灭活结肠息肉中的 SMAD4，并立即确定其后果。最后，尽管 CDX2 和 SMAD4 在促进肿瘤抑制和组织分化方面具有相似的功能，但 Aim 3 尚未研究使用新的突变小鼠来测试 CDX2 之间的遗传相互作用。结肠中的 SMAD4 可能揭示一种新的肿瘤抑制机制，现有的研究系统无法研究 CDX2 或 SMAD4 缺失对体内肿瘤染色质调节的直接后果。我们已经组装了多种结直肠癌动物模型，其中可以以精确的时间分辨率诱导转录因子敲除，因此该系统能够进行详细的基因组规模实验来探究肿瘤转录调控。肿瘤抑制转录因子、肿瘤染色质结构的调节以及肿瘤进展转录调节的新机制之间的直接联系。