Epitranscriptomic mechanism of environmental stress response and tumorigenesis

摘要 包括人类在内的所有有机体都会不断地暴露在各种造成破坏的环境介质中。 DNA和其他生物分子，从而威胁到基因组的完整性和细胞的动态平衡，导致 与癌症等各种疾病的发展有关。在过去的几年里，在NIEHS资金的支持下， 我的实验室已经进行了几项筛选研究，导致了关于RNA修饰作用的令人兴奋的发现 在紫外线辐射和砷诱导的DNA修复、细胞内稳态和肿瘤发生中，两个已知的 致癌物质。这些结果特别关注最丰富的内部mRNA甲基化，N6- 甲基腺苷(M6A)基因甲基化。然而，主要的挑战是环境代理人如何 与表位转录组的相互作用在疾病发病机制中仍然知之甚少。基于这些发现 在我们已发表的工作和未发表的发现中，我建议检验这个重要的假设： 环境的侮辱扰乱了表位转录机制，从而损害了基因组的完整性和细胞 动态平衡，导致肿瘤的发生。我的R35应用程序的重点是确定表位转录 生化系统、细胞和小鼠的环境应激反应和肿瘤发生机制 异种/原位/遗传性肿瘤模型。随着研究计划的发展，我们将建立 这些发现与人类样本的相关性。此外，我们还将扩大调查范围，探索 在皮肤细胞和上皮细胞中，RNA修饰是如何被其他环境致癌物质调节的 这些致癌物所针对的其他组织来源的细胞。我们将使用新的M6A甲基组 由我们的合作者实验室开发的测序技术，以及其他测序技术 环境方面的缩写。此外，我们将继续创造新的遗传小鼠模型，以 研究RNA修饰在环境肿瘤发生中的作用。我广泛的研究计划将继续 以下目标：(I)建立m6A RNA甲基化调节肿瘤发生的机制 在UVB辐射和砷暴露后；(Ii)发现调节m6A mRNA甲基化的新酶 在环境应激反应和肿瘤发生中的作用；(Iii)探索其他RNA修饰在 环境应激反应和肿瘤发生；以及(Iv)识别调节RNA的新分子 作为探针/治疗学的改进。由此产生的发现可以极大地扩展我们的知识，以进一步 确定环境表观转录组学在应激反应和癌症中的作用，并开辟新的 开发新的基于表位转录组学的探测/治疗方法以改进预防和治疗的机会 治疗癌症和其他疾病。

Abstract All organisms including humans are constantly exposed to various environmental agents that cause damage to the DNA as well as other biomolecules, and thus threaten genomic integrity and cellular homeostasis, leading to the development of various diseases such as cancer. During the past few years, supported by NIEHS funding, my lab has carried out several screening studies, leading to exciting discoveries on the role of RNA modifications in DNA repair, cellular homeostasis, and tumorigenesis induced by UV irradiation and arsenic, two known carcinogenic agents. These results focus particularly on the most abundant internal mRNA methylation, N6- methyladenosine (m6A) mRNA methylation. However, the major challenge is that how environmental agents interact with the epitranscriptome in disease pathogenesis remains poorly understood. Based on the discoveries made in our published work and our unpublished findings, I propose to test this overarching hypothesis: environmental insults dysregulate the epitranscriptomic machinery and thus impair genomic integrity and cellular homeostasis, leading to tumorigenesis. The focus of my R35 application is to determine the epitranscriptomic mechanism of environmental stress response and tumorigenesis in biochemical systems, cells, and mouse xenograft/orthotopic/genetic tumor models. As the research program evolves, we will then establish the relevance of these discoveries in human samples. Furthermore, we will also expand our investigation to explore how RNA modifications are modulated by other environmental carcinogenic agents, in skin cells and in epithelial cells of other tissue origins that are targeted by these carcinogens. We will employ the novel m6A methylome sequencing technology developed by our collaborator’s lab, as well as other sequencing technologies to map the environmental epitranscriptome. In addition, we will continue to create new genetic mouse models to investigate the role of RNA modifications in environmental tumorigenesis. My broad research program will pursue the following goals: (i) establish the mechanism by which m6A RNA methylation regulates tumorigenesis following UVB radiation and arsenic exposure; (ii) discover new enzymes that regulate m6A mRNA methylation in environmental stress response and tumorigenesis; (iii) explore the roles of other RNA modifications in environmental stress response and tumorigenesis; and (iv) identify new molecules that modulate RNA modifications as probes/therapeutics. The resultant discoveries can vastly expand our knowledge to further establish the role of environmental epitranscriptomics in stress response and cancer, and open up new opportunities to develop new epitranscriptomics-based probes/therapeutics to improve prevention and therapy for cancer as well as other diseases.