Research

Chemical modifications are present in almost all forms of RNA species, including messenger RNA (mRNA) and transfer RNA (tRNA). These modifications can dramatically expand the RNA alphabet through altering the nucleotide structures, changing their affinity to the partner proteins, and through base-pairing ability between complementary bases critical for RNA functions. The changes in an organism’s cells resulting from co-transcriptional or post-transcriptional chemical modifications of cellular RNA species have become appreciated than ever since the discovery of the modifications are fully reversible and mediated by enzymes. The recent studies of RNA chemical modifications have resulted in a fascinating new area of interdisciplinary science termed epitranscriptomics. The long-term objective of our research is to contribute to the chemistry understanding of RNA methylation and functional relevance at both the molecular and cellular levels. Our research program spans a broad range of protein chemistry, enzymology, nucleic acid chemistry, cell biology, epigenetics, and structural biology. We are interested in studying the mechanism by which how the RNA modifying enzymes operate and the biological impact of the dynamic status of RNA decoration with various methyl (-CH3) tags. Our on-going efforts include the studying on the regulation of mRNA and tRNA modifications; identification and function of new types of modifications in messenger RNA; the relationship between tRNA modification, tRNA fragmentation, and characterization of the multi-protein-RNA supercomplexes that govern RNA modifications and the translation process in metabolism. We seek to find the fundamental principles that will give rise to a general view of methylation across distinct RNA types, and that will lead to therapeutic targets to help to improve human life.

Recent studies identified numerous N6-methyladenosine (m6A), pseudouridine, 5-methylcytosine, 2’O methylation, and N1-methyladenosine sites in eukaryotic polyadenylated RNA. Accumulating evidence is pointing to a role for the RNA methylation program in cancer self-renewal and cell fate determination, making this a new and promising therapeutic avenue for investigation. We and others showed that there are additional modifications except for the aforementioned five modifications in messenger RNA. These new modifications in mRNA are with uncharacterized functions. Our goal is to investigate the functions of these mRNA modifications, the molecular and cellular consequences of disturbed modification status, the physiological underlie to the human metabolism regulation and pathological mechanisms by which these modifications contribute to metabolic syndromes with a focus on human glioma. The current focal points of research in the lab include the identification and characterization of the writer(s), reader(s), and eraser(s) of these new modifications. Furthermore, we are developing new sequencing methods with the goal to pinpoint these modifications at single-nucleotide resolution.

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In mammalian cells, the cleavage of tRNA is mediated by an enzyme known as angiogenin. The biological significance of angiogenin-mediated tRNA cleavage has become increasingly appreciated. tRNA cleavage occurs at different sites over different isotypes and isoacceptors, dependent on the cellular environment. The tRNA fragments, derived from various tRNA species, varied in abundance and length, are present with distinct biological functions. An apparent knowledge hole that needs immediate attention is how those tRNA fragmentation are connected to the tRNA modifications landscape. The first, and perhaps the only, documented case in this context is that the lack of m5C in tRNA is known resulting in accumulation of 5’-tRNA fragments, and as such, further induces apoptosis of neurons. Under stress conditions, for instance, hypoxia, tRNA fragments generated are shown as an active factor in the suppression of cancer progression. One of the research thrusts in the lab is to systematically look into the relationships among the tRNA-modifying enzymes, the generation of tRNA fragments under various cellular environment and human disease states, including cancer.

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Type II Diabetes Mellitus (T2DM) is a metabolic disorder characterized by insulin resistance and impaired glucose homeostasis. Over 170 million people worldwide suffer from T2DM, and the prevalence of this disease is steadily rising primarily due to overnutrition. The new insights into the molecular mechanisms underlying the correlation between obesity and T2DM are sorely needed for developing improved new therapies.

The hot spot mutations and polymorphisms in several RNA-modifying enzymes were linked to T2DM. These RNA-modifying enzymes include the methyltransferase enzymes install methylation in RNA (also known as writers) and the demethylase enzymes (aka. erasers). However, the mechanisms by which the RNA-modifying enzymes influence RNA processing and ultimately leads to T2DM disease remain elusive. A body of published results and our preliminary data allows us to form the hypothesis that the RNA-modifying enzymes need to apply tight regulation on the targeted RNAs and to synchronize the RNA species during adipocyte development. Our goal is to thoroughly analyze the possibility of an orchestrated dynamic control on RNA modifications, the molecular and cellular consequences of disturbed RNPs during adipocyte differentiation, and pathological mechanisms by which the dysregulated RNPs contribute to metabolic syndromes with an initial focus on human obesity and T2DM.

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