Integrin alpha6beta4 regulation of cancer epigenetics

DNA去甲基化机制如何靶向特定的基因组位点仍然知之甚少，然而， 对肿瘤生物学有重要意义。越来越多的证据表明， 影响表观遗传学;然而，指导这些事件的机制尚未阐明。我们有 证明了整合素α6β4显著改变转录组，使其变为侵袭性表型。的 整联蛋白调节这一过程，部分是通过调节DNA而显著改变表观基因组 选择的富含CpG的区域和基因座的去甲基化。因此，我们希望了解整合素α6β4 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 监管.对整合素α6β4如何调节DNA去甲基化的研究（由NCI R21资助）导致了 我们发现整合素α6β4利用并刺激碱基切除修复（BER）途径介导 这些表观遗传事件，但不是在细胞中，其中整合素α6β4和细胞核之间的联系， 暴露了我们还鉴定了整合素β4亚基的特异性突变， 结合到中间丝并锚定在核下，从而指示整合素- 介导的核功能改变。根据我们的初步数据和支持文献，我们 假设整合素α6β4协调信号和机械转导到驱动BER的细胞核 并导致所选基因座的DNA去甲基化，这反过来又增强了肿瘤的侵袭和转移。我们将 通过完成以下三个目标来测试我们的中心假设：1）确定整合素α6β4 细胞骨架连接影响侵袭、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，和3）定义由整合素α6β4介导的表观基因组的变化 发信号。我们希望通过阐明整合素α6β4调节细胞凋亡的基因和途径， 选择基因的去甲基化，我们将提供关键的洞察如何在基因组内的特定位点是 去甲基化以促进侵袭性和转移性转录组。

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.