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Murn Lab
For Creative Research of RNA Biology
AREAS OF INTEREST
The RNA world of cellular quiescence
Studies of cellular and molecular biology often rely on relentless proliferation of cells. However, the vast majority of cells in nature, from bacteria to cells of an adult metazoan, reside in quiescence, a state of reversible proliferative arrest that can last from a few days to several decades. Quiescence of stem cells plays critical roles in development, tissue repair, reproduction, immunity, aging, and longevity of organisms. Oncogenic changes that disrupt quiescence drive pathological proliferation. How cells enter quiescence and adapt their homeostasis to a long-lasting nondividing state is an important unsolved problem in biology. Our lab discovered that processing of specific RNA serves as a general switch that determines whether cells proliferate or enter quiescence. Genetic approaches to control this switch now allow us to induce quiescence on-demand in different mammalian cell lineages, including stem cells. We are investigating the RNA and signaling biology underlying this phenomenon and we are developing additional approaches to exploit it for fundamental and applied research.
The interface between RBPs and their effectors
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RNA-binding proteins (RBPs) regulate essentially every event in the lifetime of an RNA molecule, from its production to destruction. Whereas much has been learned about RNA sequence specificity and general functions of individual RBPs, the ways in which numerous RBPs instruct a much smaller number of effector molecules, that is, the core engines of RNA processing, as to where, when and how to act remain largely speculative. We are broadly interested in the modes of communication between RBPs and their effectors, particularly in the converging RBP–effector interactions and their roles in reducing the complexity of RNA networks (He et al, Nat Rev Genet 2023). Functional analyses of RBP–effector interactions along with the RNA-binding information allow our lab to better understand RBP activities, their regulation of biological processes, and their contribution to human diseases, including cancer and neurological disorders (Shah et al, Nat Commun 2024).
Ancient RNA-based enzymes in modern-day cells
In the course of evolution, an impressive array of multiprotein RNA processing complexes has replaced all but a few RNA-based enzymes that persist in extant cells. What attributes might be rendering these ancient catalysts superior to proteins in cells of higher organisms is an enduring puzzle. Taking deep conservation as an indicator of an important function, we are addressing these questions by employing bottom-up and top-down approaches to decipher the compositional variability, RNA targeting specificity, and regulatory scope enabled by these seemingly gratuitously complex enzymes in eukaryotes. We are currently exploring unannotated roles of two such relics, ribonuclease (RNase) P and RNase MRP, in mammalian cells.
Tissue-specific regulation of the epitranscriptome
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More that 100 distinct biochemical modifications of RNA have been discovered within a cell. Several of these RNA modifications appear to affect RNA structure or have been shown to regulate RNA processing. In analogy to the epigenome, the ensemble of functionally relevant RNA modifications has become known as the 'epitranscriptome'. Our current studies are aimed at understanding how RBPs that are 'writers' of RNA modifications can act in a tissue-specific manner, and how they may play particularly critical roles in development, functioning, and disease of the nervous system.
Method development
We are constantly on the lookout for ways to improve and broaden our ability to study RNA, including protein–RNA and RNA–RNA interactions. For instance, we recently developed a new technique, termed timeCLIP, that allows for time-resolved analysis of protein-RNA interactions in living cells (manuscript in preparation).
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