The Murn Lab
For Creative Research of RNA Biology
INSPIRATION
The Murn lab draws inspiration from the central role that RNA as life's indispensable molecule plays in biology. We are committed to solving fundamental problems in the field of RNA biology to illuminate life at the level of molecules, cells, and organisms while keeping a keen eye on potential practical implications.
We are pursuing three major unsolved problems in the field. First, as an overarching theme of our lab, we would like to understand how RNA-binding proteins (RBPs), which regulate essentially every event in the lifetime of an RNA molecule, convey their instructions to the core effectors of RNA processing. Effector interface with RBPs presents one of the most important, most regulated, most regulatable, yet least understood levels of gene regulation - we are committing a significant share of our efforts to systemic exploration of this area. Second, in one spin-off of our work on the effector interface, we seek to understand the deep evolutionary conservation and continued existence of some of the most ancient RNA-based enzymes (ribozymes) in modern-day cells. Why have these molecular relics not been replaced by the more economical protein-only enzymes? In addressing this question, we unveiled an entirely new mode of gene regulation at the RNA level that we are actively pursuing. Third, our research of RBP–effector interactions has led us to the most fundamental principle of all life - the genetic code. Though largely thought to be decoded universally, we found that RNA modifications, regulated at the RBP–effector interface, can lead to alternate decoding of specific codons. Our current efforts are geared toward understanding the mechanism of alternate decoding and how it may affect tissue development and cell function, with a particular focus on the nervous system.
Our studies make heavy use of genome-wide and computational approaches in combination with traditional biochemistry, genetics, and cell biology to allow for systems-level understanding of RNA networks and their regulatory principles. To support our research activities, we develop novel RNA technologies and receive funding from federal (NIH, NSF, DOD) and state sources.
Some of our recent stories
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A paradigm for regulation at the effector interface with RNA-binding proteins
How RBPs convey regulatory instructions to the core effectors of RNA processing is unclear. We solved this puzzle for Unkempt by dissecting its effector interface. We identified an array of linear motifs that support direct contact with two central effectors of Unkempt, the CCR4-NOT complex and PABPC. We found that the spatial arrangement, dual-purpose motifs, and obligate homodimerization are required for high-avidity effector interactions that are mandatory for the accuracy of RNA targeting, translational repression, and control of cell morphology by Unkempt. We establish the molecular assembly and functional principles of an RBP–effector interface, with general implications for the evolution and function of RBP-operated regulatory networks. Find the story at bioRxiv.
Post-transcriptional regulation at the Unkempt–effector interface.
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The nexus between RNA-binding proteins and their effectors
Beyond their recognition of RNA and their general functions, little is still known about how RNA-binding proteins (RBPs) mechanistically regulate RNA processing. Our analysis shows that numerous RBPs converge onto fewer effectors of RNA processing, forming a distinct regulatory level that contributes to the hierarchical organization of RNA networks. We find that RBP–effector interactions are dominated by contacts between short linear motifs within intrinsically disordered regions of RBPs and structured domains of effectors, allowing for high specificity but transient nature of the interactions. The RBP–effector interface serves as a versatile platform that senses intra- or extracellular stimuli and converts them into biological responses via transient or stable adjustment of RNA processing. We further find that dysregulation of contacts between RBPs and their effectors often causes human disease and that pharmacological or genetic targeting of the RBP–effector nexus carries significant therapeutic potential for neuromuscular disorders, immune disorders, and cancer. Find our story in Nature Reviews Genetics.
Organization of RNA networks.
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Post-translational modulation of RNA-binding proteins
A model for phosphorylation-dependent regulation of cell morphogenesis by Unkempt.
Reversible regulation of RBP–effector contacts is typically achieved by PTMs, of which phosphorylation has arguably garnered the most attention, particularly in the context of signal-regulated RNA processing events. The fast turnover of phosphorylation in fact renders this PTM particularly well-suited to mediating rapid responses of several types of RNA processing to a variety of signals. We found that the activity of the RNA-binding protein Unkempt, a key regulator of cell morphogenesis, is regulated by nutrient levels and growth factors via phosphorylation by mTORC1. Find out more about this story at Journal of Biological Chemistry. .
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A closer look identifies novel small regulatory RNAs
High-throughput RNA sequencing (RNA-seq) has greatly advanced small non-coding RNA discovery, but the widely used library construction protocols often give rise to biased sequencing results. We collaborated with Qi Chen's group to develop an improved library preparation method, called PANDORA-seq, that identified numerous previously unseen small regulatory RNAs primarily derived from tRNAs and rRNAs. Read the story at Nature Cell Biology.
An expanded repertoire of tsRNAs identified in mouse embryonic stem cells.
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Control of cell morphogenesis by an RNA-binding protein
Cell shape is one of the most distinctive features of all somatic cells yet little is known about how it is specified. We discovered a molecular program, controlled at the RNA level, that determines the early shape of neurons. We found that a deeply conserved RNA-binding protein, called Unkempt, coordinates an entire morphology program to establish the early bipolar shape of neurons during embryonic development of an organism. A testament to the power of post-transcriptional control and the activities of RBPs! See the story in Genes & Development.
The story of Unkempt on the cover page
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A 'heavy-duty' mode of RNA sequence recognition
Following up on our initial story on the RNA-binding protein Unkempt (see above) we wondered how the six CCCH zinc fingers of Unkempt - the largest such array of any mammalian protein - operate to recognize a relatively short stretch of RNA sequence. We found that the six zinc fingers form two bulky RNA-binding folds, each recognizing a distinct trinucleotide RNA motif. Presence of both motifs and their relative position within coding regions of targeted genes is critical for high-affinity RNA binding, which, in turn, is required for translational repression of Unkempt-target genes. Find the story at Nature Structural and Molecular Biology..
