Joseph Yesselman
@JosephYesselman
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RNA structural biologist, developing RNA-based nanomachines for therapeutic and biosensing applications.
Lincoln, NE
Joined November 2009
I have just received an NOA for my NSF CAREER " Determining The Fundamental Rules of RNA Tertiary Contact Formation"! Thank you @NSF. This would not be possible without the amazing work of my students.
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Our results provide a quantitative framework for interpreting DMS reactivity patterns in RNA. This enables more sophisticated structure prediction algorithms that consider local sequence context, non-canonical interactions, and 3D features - moving beyond base-pair predictions.
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Most significantly, we discover that DMS reactivity correlates strongly with atomic distances in non-canonical base pairs. These quantitative relationships demonstrate that DMS chemical mapping data encodes detailed information about RNA 3D structure.
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We find that 11% of non-Watson-Crick nucleotides show protection from DMS similar to Watson-Crick pairs. This protection stems from hydrogen bonding and reduced solvent accessibility. Notably, sequence context can alter reactivity up to 100-fold in specific non-canonical pairs.
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We analyzed flanking WC pairs and found structural features that determine their DMS reactivity. A-U pairs are 19-fold more reactive than G-C pairs, purine neighbors increase reactivity, and junction asymmetry correlates with higher reactivity.
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Analysis of our comprehensive dataset reveals DMS reactivity exists on a continuous spectrum rather than discrete states. We observe ~10% overlap between Watson-Crick and non-Watson-Crick nucleotides, demonstrating that simple reactivity thresholds cannot determine base-pairing.
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To correlate DMS reactivity with RNA structure, we built a massive library of 7,500 RNA constructs containing multiple junctions with known 3D structures. Our measurements are reproducible (R²=0.99), span 4 orders of magnitude, and reveal that RNA motifs have unique DMS profiles.
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🧬Excited to share our new preprint! DMS chemical mapping, a key technique for studying RNA structure. It is assumed that low DMS reactivity=WC, high=non-WC. However, analyzing 7,500 RNA structures containing known 3D structures reveals it's not simple.
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I am really excited to be giving a talk at the University of Michigan, where I received my PhD.
Join us Monday🧬October 7, 4-5 PM #RNA Innovation Seminar Series @JosephYesselman, Ph.D., @UNLincoln. “High-throughput determination of RNA tertiary contact thermodynamics by quantitative DMS chemical mapping”. @umichmedicine BSRB ABC Rooms and Zoom. Visit
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My students are making introduction videos for common lab tasks for when new students join. Here is a draft of their first video on casting and running a gel: I would love people's comments and suggestions.
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What is exciting is that it appears DMS reactivity is directly correlated with tertiary contact strength. I hope these observations are moving us to a deeper, more quantitative model of DMS reactivity. Many more papers are in the pipeline that build on this idea. Stay tuned!.
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Our paper "High-throughput determination of RNA tertiary contact thermodynamics by quantitative DMS chemical mapping" was published in NAR! (. We demonstrated that we can measure the strength of tertiary contacts with DMS chemical mapping. 1/2
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This is definitely the most true thing on twitter today.
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However if I give it a mutate version where the contact cannot form, it still thinks it forms
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It seems #AlphaFold 3 it better with RNA but still has a long way to go. Here is an new RNA not in the training set that contains a tertiary contact which it sorta gets although its slightly messed up
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We believe the work here can be generalized to other in vitro and in vivo systems. Furthermore these results help us understand the range of DMS reactivity measurements past simply high is not paired and low is paired. Thanks for reading!.
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Lastly we looked at the reactivity of the GAAA tetraloop of a single point. In this case at 7.5 mM Mg2+ and saw these measurements were even more correlated with dGs measured from RNA-MaP. This means DMS reactivity is directly correlated to 3D stability!
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These reactivitys can be used to compute the Mg1/2 which can be directed related to dG. We looked at ~100 tetraloop-receptor mutations previous characterized by @WJGreenleaf and Dan Herschlag using RNA-MaP and we saw strong agreement with our computed Mg1/2s.
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Our method (qDMS-MaPseq) can be performed with common equipment and can be done on thousands of RNAs at nucleotide resolution. Below is the individual reactivity profiles of each A/C in tetraloop/tetraloop receptor contact.
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Excited to announce a new preprint: We developed a high-throughput method to measure the thermostability of RNA tertiary contacts using DMS chemical mapping and Mg2+ titrations. We believe this method is highly generalizable to many different systems. 1/.
biorxiv.org
Structured RNAs often contain long-range tertiary contacts that are critical to their function. Despite the importance of tertiary contacts, methods to measure their thermodynamics are low throughput...
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Congrats @RDasLab @RachaelKretsch ! Excited to read!.
Tertiary folds of the SL5 RNA from the 5' proximal region of SARS-CoV-2 and related coronaviruses
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