Nearly one half of the human genome consists of transposable elements (TEs), a.k.a. ?jumping genes?; however, we know surprisingly very little about them. The rise of genomic technologies has begun to shed light on the multi-faceted functions of TEs, but interrogations of their impact on human diseases are still lacking. The majority of TEs are suppressed in somatic tissues, but some TE families are consistently re-activated in cancer. It has been revealed that TEs contribute to tumorigenesis both through active transposition and by providing alternative promoters to drive oncogene expression. However, these mechanisms may represent the tip of an iceberg. Recent works from Dr. Zhang and others show that TEs can alter higher-order chromatin architecture (insulator role) and enhance expression of nearby genes (enhancer role). These findings suggest the intriguing possibility that re-activation of TEs in cancer may similarly remodel higher-order chromatin structure and cause oncogene and tumor suppressor mis-regulation, thus contributing to tumorigenesis. This proposal aims to comprehensively characterize the landscape of re-activated TEs in cancer by leveraging public consortia data, including the cancer genome atlas (TCGA) and cancer cell line encyclopedia (CCLE). Dr. Zhang will employ genomic assays and reporter assays to determine the enhancer and insulator properties of TEs in cancer cell lines (Aim 1). Subsequently, Dr. Zhang will computationally predict and experimentally validate functional impact of TEs as cis-regulatory elements on the nearby oncogenes and tumor suppressor genes and cancer cell growth (Aim 2). Finally, Dr. Zhang will investigate the mechanisms causing TE over- expression in cancer cells (Aim 3). Overall, the results from this proposal will reveal new regulatory roles of TEs in human diseases, and expand our understanding of the mechanisms leading to gene deregulation and oncogenesis. Dr. Zhang's career goal is to lead an independent research group devoted to understanding the epigenetic dysregulation in human aging and cancer. During the K99 phase, he will continue to receive computational and experimental training from his postdoctoral mentor Dr. Ren and his advisory committee at Ludwig Institute and UC San Diego. The rigorous mentored support and results obtained in the K99 phase will facilitate Dr. Zhang's transition to independence as an investigator in the R00 phase, and lay the foundation for his future career.
Nearly half of the human genome consists of transposable elements, and many of them are consistently re- activated in various types of cancers. This proposal aims to uncover the potential enhancer and insulator roles of transposable elements and investigate the mechanism of their over expression and contribution to cancer development. The proposed project will not only expand our understanding of the cancer etiology, but also provide insights about potential treatments against aberrantly activated transposable elements.