Ninety-nine percent of RNA inside cells does not code for protein. While some noncoding transcripts have well-established regulatory functions, for instance, by repressing mRNAs or silencing transcription of an entire chromosome, the vast majority are still poorly characterized. The Kleaveland lab is fascinated by this dark matter of the transcriptome. Current work in the lab is focused on understanding how noncoding RNAs cooperate to form regulatory circuits, how noncoding RNA-based regulation contributes to development and brain function, and how long-lived noncoding RNAs like microRNAs and circular RNAs are destabilized. To tackle these questions, the lab applies classic and high-throughput molecular and biochemical approaches to mammalian cells and transgenic mice. For instance, the lab is performing systematic mutagenesis, chemical probing, and RNA-protein interaction studies of the Cyrano long noncoding RNA to determine how its sequence and structure enable Cyrano to eliminate as much as 98% of microRNA-7 in some cells. Here, Cyrano serves as an archetype for uncovering the rules that govern a phenomenon known as target-directed microRNA degradation. Knowing these rules will allow the lab to comprehensively identify RNAs that trigger microRNA degradation, predict their efficacy, and probe their functions. In another project, the lab is quantifying the localization and turnover of the Cdr1as circular RNA in primary neuronal cultures and identifying the RNA-binding proteins regulating Cdr1as. Leveraging the tools and techniques used to study a few RNAs, the lab aspires to deorphan the functions of many noncoding RNAs and ultimately determine their contributions to human health.
- ZSWIM8 and microRNA degradation in human neurogenesis
- Experimental methods to identify RNAs that trigger miRNA degradation
- Circular RNA degradation
- Structure-function of the Cyrano long noncoding RNA
- Argonaute-2 slicing activity in mammalian development
Kleaveland earned his bachelor’s degree in biology and English from Stanford University in 2001 and his M.D./Ph.D. degree in cell and molecular biology from the University of Pennsylvania’s Perelman School of Medicine, under the mentorship of Mark Kahn. Kleaveland completed his postdoctoral training at Whitehead Institute with Dave Bartel. In 2020, Kleaveland joined Weill Cornell as an Assistant Professor of Pathology and Lab Medicine.