Research

 

Dynamic regulation of RNA through chemical modifications plays a critical role in the genetic information flow in eukaryotic systems. Recent evidence suggests metabolic status of cells alters this epitranscriptomic control. Our research focus is placed on the regulation of energy homeostasis in mammals at the RNA level. We investigate co-regulation of RNA modifications, the biological consequence of altered RNA modification status, with specific emphasis on the impact in energy homeostasis during physiological and pathophysiological processes. Towards this goal, we will crack the combination code in mRNA, investigate the relationships of tRNA modifications with tRNA fragmentations, and characterize the multi-protein-RNA supercomplexes that govern RNA modifications and the translation process in metabolism. Our research program spans a broad range of protein biochemistry, enzymology, nucleic acid chemistry and biology, epigenetics, and structural biology.

 

An emerging concept in gene expression regulation is that a diverse set of modified nucleotides is found internally within mRNA, and these modifications markedly influence the fate of mRNAs in cells. 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 easer(s) of these new modifications. Furthermore, we are developing new sequencing methods with the goal to pinpoint these modifications at single nucleotide resolution.

Picture6.png

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.

Picture7.png

 

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 a number of 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.

Picture8.png