Integrin alpha6beta4 regulation of cancer epigenetics

整合素α6β4对癌症表观遗传学的调节

基本信息

批准号：
10321610
负责人：
KATHLEEN L. O'CONNOR
金额：
$ 45.67万
依托单位：
UNIVERSITY OF KENTUCKY
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：
2019-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10321610
关键词：
Actins Apoptosis Base Excision Repairs Basement membrane Bioinformatics Biometry Breast Carcinoma Cell Nucleus Cells Chromatin Clinical Complex Cytokeratin Cytoskeleton Cytosol DNA DNA Methylation DNA Repair DNA Sequence Alteration Data Enhancers Environment Epigenetic Process Event Fostering Funding GADD45A gene Gene Expression Regulation Genes Genome Heterogeneity Histones Integrin Binding Integrin alpha6beta4 Integrin beta4 Integrins Intermediate Filaments Investigation Keratin Laboratories Laminin Link Literature Malignant Neoplasms Mediating Methodology Methylation Modeling Modification Molecular Mutation Neoplasm Metastasis Nuclear Nuclear Translocation Oncogenic Pathway interactions Phenotype Post-Translational Protein Processing Process Property Regulation Research Resistance Role Signal Transduction Site Solid Specificity Testing Therapeutic Therapeutic Intervention Tumor Biology Tumor Cell Invasion Untranslated RNA Vimentin Work base breast pathology cell motility demethylation emerin epigenome falls genome-wide genomic locus innovation insight leukemia/lymphoma mechanotransduction migration next generation sequencing novel plectin prevent promoter recruit repair enzyme sensor transcriptome transcriptomics triple-negative invasive breast carcinoma tumor tumor microenvironment

项目摘要

How DNA demethylation machinery can be targeted to specific genomic loci is still poorly understood, yet has important implications for tumor biology. Mounting evidence suggests that the microenvironment influences epigenetics; however, the mechanisms guiding these events have not been elucidated. We have demonstrated that integrin α6β4 dramatically alters the transcriptome toward an invasive phenotype. The integrin regulates this process, in part, by substantially changing the epigenome through the regulation of DNA demethylation of select CpG rich regions and loci. Thus, we expect that understanding how integrin α6β4 regulates the cancer epigenome holds the key to how site-specific and mechanotransduced epigenetics are regulated. Investigations into how integrin α6β4 regulates DNA demethylation (funded by an NCI R21) led to our discovery that integrin α6β4 utilizes and stimulates the base excision repair (BER) pathway to mediate these epigenetic events, but not in cells in which the link between integrin α6β4 and the nucleus is compromised. We have also identified specific mutations in integrin β4 subunit that preventing the integrin from binding to intermediate filaments and anchoring under the nucleus, thus indicating a pathway for integrin- mediated alterations in nuclear function. Based on our preliminary data and supporting literature, we hypothesize that integrin α6β4 coordinates signal and mechano-transduction to the nucleus that drives BER and results in DNA demethylation of select loci, which in turn enhances tumor invasion and metastasis. We will test our central hypothesis through completion of the following three aims: 1) Determine how integrin α6β4 cytoskeletal linkages impacts invasion, metastasis and epigenetics, 2) Elucidate how integrin α6β4 regulates BER-mediated DNA demethylation, and 3) Define changes in the epigenome mediated by integrin α6β4 signaling. We expect that by elucidating the genes and pathways used by integrin α6β4 to modulate the demethylation of select genes, we will provide critical insight into how specific sites within the genome are demethylated to foster an invasive and metastatic transcriptome.

DNA脱甲基化机制如何靶向特定的基因组基因组基因局，但仍不了解对肿瘤生物学具有重要意义。越来越多的证据表明微环境影响表观遗传学；但是，指导这些事件的机制尚未阐明。我们有证明整联蛋白α6β4在侵入性表型上显着改变了转录组。整合素通过调节DNA的调节来部分调节这一过程精选CpG富区和基因座的脱甲基化。那我们期望理解整联蛋白α6β4 调节癌症的表观基因组是位点特异性和机械传输表观遗传学的关键受监管。对整联蛋白α6β4调节DNA脱甲基化的研究（由NCI R21资助）导致我们发现整联蛋白α6β4利用和刺激基本惊喜修复（BER）途径进行介导这些表观遗传事件，但没有在整联蛋白α6β4与核之间联系的细胞中妥协。我们还确定了整联蛋白β4亚基中的特定突变，以防止整联蛋白从与中间丝结合并在细胞核下锚定，从而表明整联蛋白的途径核功能的介导改变。根据我们的初步数据和支持文献，我们假设整联蛋白α6β4将信号和机械变量坐落到驱动BER的核并导致某些局部的DNA去甲基化，从而增强了肿瘤侵袭和转移。我们将通过完成以下三个目的来检验我们的中心假设：1）确定整联蛋白α6β4如何细胞骨架连接会影响侵袭，转移和表观遗传学，2）阐明整联蛋白α6β4如何调节 BER介导的DNA脱甲基化，3）定义了整联蛋白α6β4介导的表观基因组的变化信号。我们希望通过阐明整合素α6β4使用的基因和途径来调节选择基因的脱甲基化，我们将对基因组中的特定位点的方式提供重要的见解脱甲基化以促进侵入性和转移性转录组。