Computational and Systems Biology Studies of Human Trna Fragments and Micro RNA Isoforms and Their Involvement in Race Disparities in Triple-Negative Breast Cancer
Non-coding RNAs and their roles is a rapidly expanding field due to the discoveries facilitated by RNA-sequencing technologies. Here, two classes of these molecules are studied in depth: miRNA isoforms (isomiRs) and tRNA-derived fragments (tRFs). IsomiRs are miRNA molecules with distinct endpoints as compared to the archetype one and were shown to exhibit different properties, not only in terms of relative abundance but also in what transcripts they regulate. The full set of isomiRs was found to better describe molecular differences between breast cancer subtypes can more acquiretly be used for cancer classification than the set of archetype miRNAs. Regarding tRFs, the tRNA space on the human genome was firstly refined by uncovering the existence of numerous conspicuously-placed mitochondrial tRNA-lookalikes on nuclear chromosomes. Then a comprehensive and deterministic algorithm for their quantification was developed. Dependencies on tissue, tissue-state, disease subtype, sex, population and race were determined for both isomiRs and tRFs. IsomiRs and tRFs were found to form a cohesive network with mRNAs in normal tissue which was disrupted in triple-negative breast cancer (TNBC). In this cancer type, tRFs and isomiRs were linked with distinct mRNAs and biological processes. Specifically, tRFs were associated with energy metabolism, ribosomal proteins and cell signaling, while isomiRs with immune system responses and related signaling. Regarding race disparities in TNBC, systems analyses suggest a considerable contribution of both types of non-coding RNAs in the racially-dependent mRNA profile as well as in their contribution on regulating metastatic pathways. Collectively, the current study comprehensively elucidates the repertoire of isomiRs and tRFs, unravels their dependencies and provides important insight in their contributions on shaping the molecular biology of complex diseases.
Telonis, Aristeidis G, "Computational and Systems Biology Studies of Human Trna Fragments and Micro RNA Isoforms and Their Involvement in Race Disparities in Triple-Negative Breast Cancer" (2018). ETD Collection for Thomas Jefferson University. AAI10815754.