Small RNAs extend far beyond miRNAs, encompassing diverse species derived from tRNAs, rRNAs, and other sources (Y RNA, small nuclear RNA, small nucleolar RNA, vault RNA, etc). PANDORA-seq has revealed that most sncRNAs are noncanonical tRNA- and rRNA-derived species (i.e., tsRNAs and rsRNAs) that dominate across tissue/cell types and organisms. To chart this complexity, our lab develops bioinformatics tools that redefine how sncRNAs are discovered and quantified. The SPORTS platform provides an annotation/profiling pipeline for mapping heterogeneous sncRNAs with high precision. Recently, the FUSION tool enables family-level integration of sncRNA data, improving differential analysis in noisy or low-replicate samples. These tools establish a foundation for multi-omics integration and RNA dynamics modeling, offering a deeper and more accurate view of the small RNA world.
Beyond RNA Interference: Discovering New Functional Paradigms
While miRNAs and siRNAs regulate genes via RNA interference (RNAi), our research suggests that many sncRNAs act through aptamer-like mechanisms, folding into structured motifs that bind proteins, lipids, or metabolites, which is independent of base pairing. Our studies trace these functions back to the RNA world, where tsRNAs likely predated canonical RNAi. These RNAs, shaped by chemical modifications, modulate translation, ribosome assembly, and even intergenerational inheritance. A growing focus is their interaction with Toll-like receptors (TLR7/8), key immune sensors of single-stranded RNA. A Sequential Activation Hypothesis is accordingly proposed, linking stress-induced tsRNAs and rsRNAs to autoimmune activation and sex-biased diseases such as lupus. This conceptual bridge, from microbial evolution to human immunity, reframes how we think about small RNAs as molecular sentinels connecting metabolism, immunity, and inheritance.
Translating RNA Code into Precision Medicine
The intricate language of sncRNAs, i.e., their sequences, structures, abundance, and modifications, offers powerful insights into biomarker discovery and therapeutic design. Using PANDORA-seq along with SPORTS and FUSION, we may identify disease-associated sncRNA signatures in biofluids such as serum and sperm, advancing non-invasive diagnostics for metabolic, autoimmune, and reproductive disorders. Particularly, our computational module within the FUSION tool enables single-case (1-on-1) studies, ideal for personalized medicine. Through collaborations bridging computation and clinic, we aim to transform RNA code into actionable medical knowledge, advancing the next generation of RNA-driven precision medicine.
The Zhou Lab focuses on computational biology and bioinformatics to unravel the complexities of small non-coding RNAs (sncRNAs). Through collaborations with other researchers, particularly with Dr. Qi Chen, we apply and/or develop cutting-edge tools and analytical frameworks to explore sncRNA biogenesis, functions, and applications. Our work bridges molecular evolution, biology, and translational medicine, revealing the roles of these ancient RNA molecules in bioligical processes and diseases. By investigating sncRNA sequences, structures, abundance, and modifications collectively, we aim to decode the RNA code and its implications for precision medicine.
Expanding the Universe of Small RNAs through Computational Innovation
