Epitranscriptomic mechanism of environmental stress response and tumorigenesis

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 Based on the discoveries made in our published work and our unpublished findings, I propose to test this overarching hypothesis: environmental insults dysregulate the epitranscriptomic machinery and thus impair genomic integrity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.