“Investigating metabolic-epitranscriptomic crosstalk in health and disease”
Christina Fitzsimmons, BBT Faculty Candidate
Postdoctoral Research Associate, Harvard University
Thursday, February 20th, 12:00 PM
Gateway 1002
(Pizza will be served)
Metabolic reprogramming is a hallmark of cancer that facilitates changes in many processes. Mutations in the Citric Acid Cycle enzyme fumarate hydratase lead to fumarate accumulation and cause hereditary leiomyomatosis and renal cell cancer (HLRCC), a rare disease that can lead to a highly aggressive kidney cancer. Fumarate accumulation can inhibit a number of epigenetic enzymes in the 2-oxyglutarate-dependent dioxygenases family, impacting DNA and histone demethylation. However, the link between fumarate accumulation and RNA post-transcriptional modifications remains undefined. Here, we determine the consequences of fumarate accumulation on RNA demethylases. By evaluating multiple RNA modifications, we show fumarate accumulation alters the activity of demethylases acting upon N6-methyladenosine (m6A), while the demethylases acting upon 5-formylcytosine (f5C) in mitochondrial RNA are unaffected. The observation that metabolites may modulate subsets of RNA-modifying enzymes offers new insights into their regulatory effects as well as potential strategies for therapeutic intervention. Future work will focus on the intersection of metabolism and epitranscriptomic gene regulation across biological scales.