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 去甲基化机制如何靶向特定基因组位点仍知之甚少，但越来越多的证据表明微环境对肿瘤生物学具有重要意义。影响表观遗传学；然而，我们尚未阐明指导这些事件的机制。证明整合素 α6β4 显着改变转录组向侵袭性表型转变。整合素在一定程度上通过调节 DNA 显着改变表观基因组来调节这一过程因此，我们期望了解整合素 α6β4 的去甲基化过程。调节癌症表观基因组是位点特异性和机械转导表观遗传学如何发挥作用的关键对整合素 α6β4 如何调节 DNA 去甲基化的研究（由 NCI R21 资助）导致。我们发现整合素α6β4利用并刺激碱基切除修复（BER）途径来介导这些表观遗传事件，但不在整合素 α6β4 与细胞核之间的联系存在的细胞中我们还发现了整合素β4亚基的特定突变，可以阻止整合素的发挥。与中间丝结合并锚定在细胞核下，从而表明整合素的途径根据我们的初步数据和支持文献，我们确定了核功能的介导改变。整合素 α6β4 协调信号和机械传导到驱动 BER 的细胞核并导致选定位点的 DNA 去甲基化，从而增强肿瘤的侵袭和转移。通过完成以下三个目标来检验我们的中心假设：1）确定整合素α6β4如何细胞骨架联系影响侵袭、转移和表观遗传学，2) 阐明整合素 α6β4 如何调节 BER 介导的 DNA 去甲基化，以及 3) 定义由整合素 α6β4 介导的表观基因组变化我们期望通过阐明整合素 α6β4 用于调节的基因和途径。选定基因的去甲基化，我们将提供关于基因组内特定位点如何变化的重要见解去甲基化以培养侵袭性和转移性转录组。