BME Seminar Series | Single Molecules Come Into Focus: Every Riboswitch Nucleotide Counts in Bacterial Gene Regulation
by Allison Lyne | Mar 21, 2025 | SBHSE Events
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Date(s) - 03/21/2025
9:00 am - 9:50 am
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Nils Walter, PhD
Professor of Chemistry, Biophysics, and Biological Chemistry, Department of Chemistry, University of Michigan
Date: Friday, March 21, 2025
Time: 9:00 – 9:50 a.m., SCOB 228
Faculty Host: Shaopeng Wang
Abstract: Non-coding RNAs (ncRNAs) represent a vast and largely untapped dimension of biology, accounting for more than 90% of the transcriptional output of the human genome. This challenges earlier notions that much of our DNA is mere “junk.” With over 80,000 unique ncRNAs identified in human cells, these molecules play intricate roles in genome maintenance, processing, and regulation. Nature, akin to modern nanotechnology, leverages RNA to create nanoscale machines with remarkable architectural and functional complexity. We are using advanced fluorescence microscopy techniques, such as single-molecule fluorescence resonance energy transfer (smFRET) and super-resolution imaging, for probing these RNA structures in real-time with nanometer precision. Among these captivating ncRNA elements are riboswitches—highly structured RNA elements embedded in the 5’ untranslated regions of bacterial mRNAs. These motifs regulate gene expression by folding co-transcriptionally to bind small molecules or ions, acting as precise molecular switches. For instance, manganese-sensing riboswitches utilize a central, adaptable RNA helix as a molecular fulcrum, integrating diverse signals to achieve finely tuned bacterial gene regulation. The Mn2+ riboswitch exemplifies a key feature of riboswitch architecture: while its upstream aptamer region is highly conserved to ensure robust ligand binding, the downstream expression platform often exhibits lower conservation due to its species-specific interactions with protein effectors. This nuanced functional adaptability highlights the limitations of relying solely on sequence conservation to predict the functional importance of nucleotides within riboswitches. Our research employs single-molecule imaging and biochemical techniques to reveal how RNA folding dynamically couples with gene expression regulation. Riboswitches, as we uncover, epitomize the intricate interplay between RNA structure and function, enabling exquisite regulatory precision. These findings illuminate the untapped potential of ncRNAs as vital players in life’s processes, expanding our understanding of biological regulation and paving the way for innovative therapeutic strategies.
Biosketch: Nils G. Walter is currently the Francis S. Collins Collegiate Professor of Chemistry, Biophysics, and Biological Chemistry in the College of Literature, Science and the Arts of the University of Michigan in Ann Arbor, Michigan. He cofounded and currently codirects the Center for RNA Biomedicine at Michigan, developing a thrust in RNA Therapeutics. He started his career by receiving his “Vordiplom” (B.S.) and “Diploma” (Masters) from the Technical University of Darmstadt and earned his Dr. Ing. while studying molecular in vitro evolution of DNA and RNA with Nobel laureate Manfred Eigen at the Max-Planck-Institute for Biophysical Chemistry, Göttingen. For his postdoctoral studies, he turned to RNA enzymes under the guidance of John M. Burke at the University of Vermont in Burlington, Vermont. His research interests focus on gene regulation by noncoding RNAs through the lens of single molecule techniques and applications in drug discovery. Based on this work, he received the Otto-Hahn medal for Outstanding Researchers of the Max-Planck Society (1995), a Feodor-Lynen Postdoctoral Research Fellowship from the Alexander von Humboldt Foundation (1995), a Camille Dreyfus Teacher-Scholar Award (2004), was elected a Member of the American Academy of Arts & Sciences (2011), received the Faculty Recognition (2013) and Harold R. Johnson Diversity Service Awards (2015) from the University of Michigan, and became the first RNA Society Mid-Career Award recipient (2017). He has been privileged to receive long-standing funding from the National Institutes of Health, National Science Foundation, and Foundations, and has previously founded a biotech startup in the molecular diagnostics space.