Research questions

Chemical modifications occur naturally on almost all RNA subtypes, including rRNAs, tRNAs, mRNAs and small RNAs. They play important roles in RNA metabolism and gene regulation. RNA modifications are catalyzed by specialized enzymes - writers ("add" modifications) and erasers ("remove" modifications). Importantly, many RNA modifying enzymes have dysregulated expression in human disease, including cancers, neurodevelopmental disorders and mitochondria disorders. RNA modifications can be affected by endogenous or exogenous environment and metabolism to modulate gene expression output via epigenetic mechanisms.


Direction 1. Genomics tools to detect RNA modifications in human disease

Despite the prevalence and abundance of RNA modifications, it has been a major challenge to profile the genome-wide distribution of RNA modifications (read this recent commentary in Nature Genetics). New approaches are still being developed to tackle this important question. Epitranscriptomics, or RNA epigenetics, was named Method of the Year 2016. We use reverse transcription (RT)-specific signature from Next-Generational Sequencing (NGS) data to identify and quantify site-specific RNA modifications at base resolution. Such modification signatures were found on both protein-coding mRNAs and non-coding RNAs (tRNAs, rRNAs and small RNAs). Recently we reported global epitranscriptomic changes in bladder cancer tumor samples compared to adjacent normal samples. We will continue to apply genomics tools to identify RNA modification patterns that are altered in cancer cells, cancer tissues and biofluids with a particular focus on glioma and bladder cancers. In addition to cancer biology, we also have several ongoing collaborations on aging, neurological disorders and stress biology


Direction 2. Substrates and molecular functions of RNA-modifying enzymes

Many RNA-modifying enzymes have dysregulated expression in human disease, including cancers, neurological disorders and mitochondria disorders. However, a huge number of RNA-modifying enzymes have not yet been studied or identified in humans. In addition, we also do not fully understand the molecular function of RNA modifications on specific RNA molecules. To begin understanding the disease-relevant RNA-modifying enzymes, it will be important to investigate (1) whether dysregulated expression of RNA-modifying enzymes leads to altered RNA modifications, (2) how specific RNA substrates are recognized by the RNA-modifying enzymes, (3) how RNA modification affects RNA metabolism on specific RNA substrates, (4) whether and how RNA metabolism contributes to the pathogenesis. Addressing these questions will provide rationale and mechanistic basis for targeting RNA-modifying enzymes as therapeutic targets. For example, we recently found the writer enzyme TRMT6/61A and its enzymatic product 1-methyladenosine is up-regulated in bladder cancers and affects gene-silencing activity of small RNAs, which contributes to global gene regulation and unfolded protein response that is important for cancer cells to survive. 


Direction 3. tRNA (transfer RNA) homeostasis and proteostasis

tRNA (transfer RNA) is the adaptor molecule in translating mRNA into protein. tRNAs represent remarkable examples for RNA modification research: each tRNA harbors ~ 13 RNA modifications per molecule. Interestingly, tRNAs also have non-canonical functions outside of their role in protein synthesis (read this review article from Annual Review of Genetics). One example of the non-canonical functions is that tRNAs give rise to tRNA-derived fragments (tRFs) with similar size and function as microRNAs. We are curious about the balance between canonical vs non-canonical functions of tRNAs and how RNA modification plays a role in this homeostasis. In addition, tRNAs have great potential in therapeutics to overcome mistranslation (error in protein synthesis) in many human diseases (read this recent review from Nature Biotechnology).