Samie R Jaffrey   Professor of Pharmacology

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The Jaffrey lab is interested in identifying RNA regulatory pathways that control protein expression, especially in neurodevelopmental disorders such as mental retardation and autism. We showed that the cause of the abnormal gene silencing that causes the neurodevelopmental disorder Fragile X syndrome involves a novel pathway in which trinucleotide repeat RNA hybridizes to complementary DNA sequences. These studies identified a novel mechanism of epigenetic regulation that may be broadly relevant to repeat expansion disorders. Our work has also elucidated novel RNA-based pathways that underlie axon guidance and circuit formation in the brain, particularly by controlling local translation. We use novel microfluidic techniques to harvest axons for proteomics and molecular biology analysis, which has allowed us to describe some of the first axonally localized mRNAs and their roles in axon guidance and other aspects of neuronal development, including retrograde signaling. These studies have uncovered a striking role for local RNA degradation through the nonsense-mediated RNA decay pathway in shaping the axonal RNA population and regulating local translation.

Our laboratory founded the field of mRNA “epitranscriptomics,” i.e., the study of the role and function of mRNA base modifications. We are particularly interested in the mRNA modification N6-methyladenosine (m6A). Our transcriptome-wide map of m6A was the first global analysis of an mRNA base modification and helped to initiate widespread interest in m6A as a regulatory mechanism for mRNA and ncRNAs. We found that m6A a widespread modification that occurs in over 7000 transcripts in cells. We showed that m6As in mRNAs can markedly enhance mRNA translation and that this mechanism mediates stress-mediated mRNA translation. We also recently showed that numerous mRNAs contain an additional modification near their 5’ caps called N6,2’-O-dimethyladenosine (m6Am). We are determining how m6A, m6Am, and other nucleotide modifications control mRNA and protein expression in diverse cellular and disease contexts.

In addition to our interest in studying the molecular biology of RNA processing, we also study the localization of RNAs in cells, and how this process is misregulated in diverse diseases. Imaging RNAs in live cells is challenging due to a lack labeling approaches analogous to GFP. To resolve this issue, we developed “RNA mimics of GFP.” These are short RNA sequences that bind and activate the fluorescence of otherwise nonfluorescent small molecules. We chemically synthesized variants of the fluorophore in GFP, and identified specific RNA sequences that bind them to form RNA-fluorophore complexes with GFP-like functionality. A green fluorescent RNA-fluorophore complex, called Spinach, can be tagged onto RNAs to image their movements in cells. Spinach and related tags provide the opportunity to gain the same types of insights into RNA as GFP has provided for proteins.

We have extended the Spinach technology to make a novel class of biosensors. Cellular signaling typically involves dynamic changes in signaling molecules, making it important be able to image these changes in living cells in real time. However, creating sensors is typically difficult or impossible using current protein-based technologies. We generated RNAs that bind to specific intracellular metabolites, and then fused them to Spinach so that Spinach’s fluorescence is dependent on the cellular concentrations of these targets. These RNA-based biosensors enable metabolite imaging in live cells. Because RNAs that bind virtually any target can be rapidly generated, our imaging technology has the potential to enable cellular imaging of virtually any biomolecule.

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Jaffrey Lab Website: Jaffrey Lab


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  • Weill Cornell Medical College, Cornell University