Discovery and Characterization of Small Noncoding RNAs and Their Regulatory Networks in Complex Diseases
Date of Award
Doctor of Philosophy (PhD)
MicroRNAs (miRNAs) and endogenous small interfering RNAs (endo-siRNAs) are classes of small noncoding regulatory RNAs (sncRNAs), which play critical roles in gene regulation for many biological processes in eukaryotic organisms including mRNA cleavage, RNA degradation, translation inhibition, and DNA methylation. miRNAs in particular have been shown to be essential gene regulators that broadly contribute to disease pathogenesis such as cancer. In this dissertation, we first develop computational methods to identify a variety of small noncoding RNA (sncRNA) species, which include canonical and noncanonical miRNAs in animals, as well as small interfering RNAs in plants.
We have conducted a meta-study to characterize 5'-end miRNA isoforms (5'-isomiRs), which originate from the same genomic loci of major miRNAs, in four animal species. We observe several features of 5'-isomiRs including the arm preference of 5'-isomiRs, and structural difference between miRNA hairpins with or without 5'-isomiRs. These features of 5'-end isoform deepens our understanding of the diversity of miRNAs as well as their plasticity in gene regulation and potential broad function in complex diseases.
With the small RNAs identified and well-characterized, it is practically important to study what the roles of these sncRNAs are in disease pathogenesis and stress-challenged conditions. We have applied differential-expression and network-based methods to explore the unclear roles of small RNAs in disease and stress conditions including human psoriasis disease, cold-acclimated cassava, and human melanoma.
In psoriasis, our studies revealed a large perturbation of small noncoding RNA expressions via differential expression analyses between disease and normal skin. In cold-acclaimed cassava, we showed that small RNAs including miRNAs and siRNAs altered their expressions in response to the cold stress. Thirdly, we expand the scope of our studies to miRNA regulatory networks in human melanoma. We applied systems biology approaches to model the perturbed miRNA regulatory networks, as well as developing computationally efficient methods to identify biologically meaningful patterns such as network modules.
Li Ding, Ju Tao, Ting Wang