Center for RNA Biomedicine

RNA Innovation Seminar: Gal Haimovich, Weizmann Institute of Science
2023-02-13 12:00 - 13:00 (America/Detroit)
“Why Did the RNA Cross the Nanotube? Many questions and (some) answers on tunneling-nanotube medicated RNA transfer between mammalian cells”
Gal Haimovich, Ph.D.
Assistant Staff Scientist
Department of Molecular Genetics
Weizmann Institute of Science
Virtual only: zoom link
Abstract: RNAs have been shown to undergo transfer between mammalian cells, though the mechanism behind this phenomenon and its overall importance to cell physiology is not well understood. We found that full-length mRNAs and lncRNAs undergo direct cell-cell transfer via cytoplasmic extensions called tunneling nanotubes (TNTs), which connect donor and acceptor cells. Despite 10 years of research, there are still major questions about this process such as which RNAs are transferred, what is the mechanism, how is this process regulated and what does the RNA do on the other side? I will review the evidence for TNT-mediated RNA transfer, discuss the technical challenges in this field, and provide some answers to these questions.

RNA Innovation Seminar: Jane Jackman, Ohio State University
2023-02-27 16:00 - 17:00
“A Complicated Family: Conserved & Distinct Functions of tRNA Methyltransferases from Yeast to Humans”
Jane Jackman, Ph.D.
Professor of Chemistry & Biochemistry
Ohio State University
In-person: BSRB, ABC seminar rooms / zoom link
Abstract: RNA modifications are now known to be a ubiquitous and important feature of cellular RNAs. tRNA are among the most heavily modified of RNA species, with a large network of often highly conserved enzymes dedicated to introducing distinct modifications into specific subsets of tRNAs in each organism. The expanding number of technological approaches to mapping tRNA modifications has enabled an explosion of information about the types and locations of modifications in many biological systems, but functional information about many modifications has lagged. The tRNA methyltransferase Trm10 is a SPOUT family RNA methyltransferase that is absolutely conserved throughout Archaea and Eukarya, but exhibits markedly different substrate specificities for nucleotide and tRNA substrates in different biological contexts. However, the molecular basis for these distinct substrate specificities has not been demonstrated. Moreover, despite multiple phenotypes associated with loss of Trm10 N1-methylation, including a role in human disease, the biological impact of Trm10 modification is not understood. We have taken a comprehensive approach utilizing enzymes from diverse organisms from Archaea to humans and multiple eukaryotic model systems to identify conserved and unique mechanistic and functional features of this essential family of tRNA methyltransferases.

RNA Innovation Seminar: Lori Isom, Chair, Department of Pharmacology
2023-03-06 16:00
“Dancing to a Different Tune: TANGO Provides Hope for Dravet Syndrome”
Lori Isom, Ph.D.
Chair, Department of Pharmacology
Maurice H. Seevers Collegiate Professor of Pharmacology
Professor of Molecular and Integrative Physiology
Professor of Neurology, University of Michigan Medical School
In-person: BSRB, ABC seminar rooms / zoom link
Abstract: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by high seizure frequency and severity, intellectual disability, and a high risk of sudden unexpected death in epilepsy (SUDEP). Most DS patients carry de novo variants in SCN1A leading to haploinsufficiency of the voltage-gated sodium channel a subunit Nav1.1. Scn1a +/- DS mouse models recapitulate many patient phenotypes, including severe seizures and SUDEP. DS mice have reduced excitability of parvalbumin-positive (PV+) fast-spiking interneurons, leading to disinhibition. Targeted Augmentation of Nuclear Gene Output (TANGO) was developed by our collaborators at Stoke Therapeutics to increase protein expression in diseases of haploinsufficiency using antisense oligonucleotide (ASO) technology. TANGO targets naturally occurring, non-productive alternative splicing events to reduce non-productive mRNA and increase productive mRNA and protein of the target gene by upregulating the wild-type allele. This approach has provided a unique opportunity to develop novel therapeutics to treat DS. We showed previously that a single, intracerebroventricular (ICV) dose at postnatal day (P)2 of the ASO STK-001, generated using TANGO technology to prevent inclusion of a nonsense-mediated decay or poison exon in Scn1a, exon 20N, increased productive Scn1a transcript and Nav1.1 expression and reduced the incidence of electrographic seizures and SUDEP in a mouse model of DS (SCIENCE TRANSLATIONAL MEDICINE, 2020, Vol 12, Issue 558, DOI: 10.1126/scitranslmed.aaz6100). Interestingly, de novo variants in SCN1A exon 20N were shown by others to increase its inclusion, resulting in haploinsufficiency and DS pathology in patients and in a mouse model. Our preclinical work led to a series of on-going clinical trials for STK-001. Here, we investigated the mechanism of a surrogate ASO that also targets exon 20N, ST-1001, in DS mouse brain. We tested the effects of a single ICV injection of ST-1001 at P2 on the subsequent electrophysiological properties of cortical pyramidal and PV+ fast-spiking interneurons in Scn1a +/- DS and Scn1a +/+ wild-type littermate control mice at P21-25. We show that, in untreated DS mice, intrinsic action potential (AP) firing properties of cortical pyramidal neurons were unchanged compared to controls while AP firing properties of PV+ interneurons showed depolarization block. In addition, sodium current density was reduced in DS PV+ interneurons. The frequency, but not amplitude, of inhibitory post-synaptic currents recorded in DS cortical pyramidal neurons was also reduced, suggesting reduced GABA release from interneurons. Single-dose ST-1001 ASO administration restored excitability and sodium current density in PV+ DS interneurons as well as restored GABAergic signaling to cortical pyramidal neurons. This new work provides key mechanisms for further development of precision medicine approaches to treat patients with DS and related developmental and epileptic encephalopathies. Our next experimental plan will include testing ST-1001 in a newly developed CRISPR transgenic rabbit model of DS as well as in DS patient-derived induced pluripotent stem cell neurons.

RNA Innovation Seminar: Haiyuan Yu, Cornell University
2023-04-10 16:00 - 17:00
“Dissect Enhancer Architecture and Map Regulatory Genomic Landscape Across Diverse Cell and Tissue Types Through Nascent Transcriptome Studies”
Haiyuan Yu, Ph.D.
Tisch University Professor
Department of Biological Statistics and Computational Biology
Weill Institute for Cell and Molecular Biology
Director, Center for Innovative Proteomics (CIP@Cornell)
In-person: BSRB, ABC seminar rooms / hybrid link
Abstract: Recent studies have shown that both enhancers and promoters can recruit RNA pol II and initiate transcription. The short half-life nature of enhancer RNAs (eRNAs) makes detection of distal initiation events challenging. Through systematic comparison of RNA sequencing assays, we find that nascent transcriptome assays, PRO-cap and PRO-seq, have great sensitivity and specificity in detecting eRNA transcription genome-wide. In fact, we find that, unlike histone marks, divergent transcription of eRNAs is a critical mark for all active enhancers genome-wide. Moreover, nascent transcription precisely delineates the sequence architecture of enhancers, whereby transcription start sites (TSSs) serve as critical anchors in revealing motif positioning within enhancers and their boundaries. By leveraging our high precision and sensitivity nascent transcriptome PRO-cap and PRO-seq assays, we mapped the active transcriptional regulatory landscape across ~200 tissue and cell types of the human body with unprecedented resolution and depth. This information is used to quantify gene transcriptional activity and to identify and delineate transcription regulatory elements, including both enhancers and promoters that are cell-type-specific and ubiquitous. These findings are critical in modeling putative enhancer-promoter connectivity and in speeding the identification of potential disease-associated noncoding variants in regulatory regions.

RNA Innovation Seminar: Julius B. Lucks, Northwestern University
2023-04-17 16:00 - 17:00
“RNA Synthetic Biology: Towards an Era of RNA Design for Biology & Global Health”
Julius B. Lucks, Ph.D.
Professor & Associate Chair, Chemical & Biological Engineering
Co-Director, Center for Synthetic Biology
Northwestern University
In-person: BSRB, ABC seminar rooms / hybrid link
Abstract: RNAs are emerging as a powerful substrate for engineering cellular behavior. As with all biomolecules, RNA function is intimately related to its structure, since RNA can adopt structures that selectively modulate gene expression. Central questions in biology & bioengineering then are: How do RNAs fold inside cells?; and How can we engineer these folds to control gene expression? In this talk, I will present our work at the interface of these two questions and share results that are beginning to uncover design principles for understanding natural RNAs and engineering RNAs for an array of applications in biomanufacturing and human health. I will focus on our recent work in understanding how riboswitch RNAs make regulatory decisions “on the fly” during the process of transcription, how we can use riboswitches as biosensors, and our recent development of a new synthetic biology biosensing platform that allows rapid, field-deployable diagnostics for a range of compounds important to our health and the environment.
RNA, RNA folding, RNA synthetic biology, Riboswitches, Cell-Free Synthetic Biology

RNA Innovation Seminar: Eric Wang, University of Florida
2023-05-15 16:00 - 17:00
“Repeat Expansions Instigate Supply Chain Issues in the Nucleus & Cytoplasm”
Eric Wang, Ph.D.
Associate Professor
Molecular Genetics & Microbiology
Center for Neurogenetics
University of Florida
In-person: BSRB, ABC seminar rooms / hybrid link
Keywords: Repeat expansions, myotonic dystrophy, RNA biology, RNA splicing, RNA localization, microscopy

RNA Innovation Seminar: Lydia Contreras, UT Austin
2023-06-05 16:00
“Mapping Novel RNA Regulatory Networks”
Lydia Contreras, Ph.D.
Professor-Chemical Engineering
Interdisciplinary Life Science Graduate Program
University of Texas at Austin

In-person: BSRB ABC Seminar Rooms / hybrid link
Abstract: While advances in omics-based technologies has led to the discovery of hundreds of sRNAs, their identification and characterization has lagged. Even in the model gram-negative organism, Escherichia coli, only ~40% and 60% of sRNAs have had at least one transcriptional regulator or post-transcriptional target confirmed, respectively. Additionally, the mechanistic roles of RNA-binding proteins in sRNA regulation remains elusive. This gap can be partly attributed to the selective nature of corresponding high-throughput techniques that typically rely on traditional sRNA features, such as basic promoter-based transcriptional regulation and dependence on RNA binding proteins for target activity. Additionally, lowly expressed sRNAs in commonly tested conditions are oftentimes missed. To better characterize these non-traditional and elusive sRNAs, we devised a holistic multi-tiered approach using in vivo omics datasets over a variety of cellular conditions. In this talk, we will describe our recent advances in developing high throughput approaches that allow for the simultaneous in vivo characterization of functional regions within RNA molecules. We will describe how RNA insights obtained from these synthetic probing approach can be used in the basic characterization of newly discovered RNAs and in the discovery of novel RNA mechanisms. The talk will also highlight our use of these methods in conjunction with new biophysical model and machine learning approaches for expanding our understanding of sRNA-regulation.

RNA Innovation Seminar: Junjie Guo, Yale University School of Medicine
2023-06-19 16:00 - 17:00
RNA Plasticity in Neuronal Health & Disease
Junjie Guo, Ph.D.
Assistant Professor
Department of Neuroscience
Yale University School of Medicine
In-person: BSRB, ABC seminar rooms / hybrid link
Abstract: Spatial and temporal regulation of gene expression at both transcriptional and post-transcriptional levels underlies the development and functions of the nervous system, whereas dysregulated gene expression is often implicated in neurological disorders. My lab has been interested in the roles of post-transcriptional mRNA regulation in diversifying the functional output of neuronal gene expression. In this talk, I will discuss our ongoing work on understanding the pathophysiological mechanisms by which disease-associated nucleotide repeat expansion disrupt neuronal health. I will also discuss our new work on the unexpected plasticity of N-terminal signal sequences and the role of alternative mRNA translation initiation in tuning this plasticity.
Keywords: RNA processing, mRNA translation, signal sequence, synapse, neurodegeneration

RNA Innovation Seminar: Graham Erwin, Stanford University
2023-09-11 16:00 - 17:00
“Discovering and Targeting Repeat Expansions in Human Disease”
Graham Erwin, Ph.D.
Stanford Cancer Institute Postdoctoral Fellow
Department of Genetics
Stanford University

In-person: BSRB, ABC seminar rooms / hybrid link
Abstract: Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), is known to cause more than 50 diseases. However, repeat expansions are often not explored beyond neurological and neurodegenerative disorders. Here, I will discuss efforts to identify and target repeat expansions in human disease, with a focus on neurodegenerative disease and cancer.

Researchpalooza
2023-09-13 11:00 - 14:00
Stop by the CRB booth (#1) and the SMART Center (#2) on September 13 at the Researchpalooza event!

RNA Innovation Seminar: Jeffrey Barrick, UT at Austin
2023-09-25 16:00 - 17:00
“Turning Bugs into Features: Engineering and Evolving Insect Symbiont-Mediated RNA Interference”
Jeffrey Barrick, Ph.D.
Associate Professor of Molecular Biosciences
University of Texas at Austin

In-person: BSRB, ABC seminar rooms / hybrid link
Abstract: Many insects have co-evolved associations with microbial symbionts that are more consequential than our relationship with the human microbiome. These symbionts may live within insect cells, be inherited across generations, and support host survival. My research group and our collaborators have developed genetic toolkits for engineering diverse bacterial symbionts associated with flies, aphids, bees, and other insects. Because of their important and integrated functions, engineered symbionts can be used to study insect biology, protect beneficial insects, and prevent pests from vectoring disease. Recently, we have examined how culturable “protosymbiont” strains of Serratia symbiotica colonize aphids and demonstrated that they are transmitted to offspring. We are now attempting to attenuate the pathogenicity of these strains to initiate new stable symbioses. In other work, we have shown that the honey bee gut symbiont Snodgrassella alvi can be engineered to express double-stranded RNAs that induce a targeted RNA interference response in their hosts. These engineered symbionts can be used to knock down expression of bee genes as a tool for functional genomics. We have also used double-stranded RNA expression by symbionts to prime the bee immune system against viral infection and induce a self-killing response in parasitic Varroa mites that feed on bees in order to protect pollinator health.

"Awakenings" Film Screening and Panel Discussion at the Michigan Theater
2023-09-27 18:00 - 21:00
“Awakenings” (1990)
The victims of an encephalitis epidemic many years ago have been catatonic ever since, but now a new drug offers the prospect of reviving them.
Join us for a pre-film panel discussion at 6:00 PM with neurology and neurologic disease physicians and scientists from University of Michigan’s Center for RNA Biomedicine: Michelle Hastings, Ph.D.; Maria G. Castro, Ph.D.; Christiane Wobus, Ph.D.; Henry Paulson, M.D., Ph.D.; Peter Todd, M.D., Ph.D.; and moderated by Nils G. Walter, Ph.D.

Film screening will begin at 7:00 PM. The story of a doctor’s extraordinary work in the Sixties with a group of catatonic patients he finds languishing in a Bronx hospital. Speculating that their rigidity may be akin to an extreme form of Parkinsonism, he seeks permission from his skeptical superiors to treat them with L-dopa, a drug that was used to treat Parkinson’s disease at the time. From director Penny Marshall and starring Robert De Niro and Robin Williams.
121 minutes. Drama. PG-13.
$10.50 General | $8.50 Students, Seniors, U.S. Veterans | $8 MTF Members

Presented with the University of Michigan Center for RNA Biomedicine, Michigan Medicine and Michigan Theater Foundation

RNA Innovation Seminar: Guizhi (Julian) Zhu, University of Michigan
2023-10-09 16:00 - 17:00
“Engineer and deliver nucleic acid immunotherapeutics and vaccines – a focus on small circular mRNA (circRNA) vaccines”
Guizhi (Julian) Zhu, Ph.D.
Ara G. Paul Associate Professor of Pharmaceutical Science
University of Michigan

In-person: BSRB, ABC Seminar Rooms / hybrid link
Abstract: Our ultimate research goal is to develop clinically translatable nucleic acid therapeutics and vaccines, along with their delivery systems. In this talk, we will mainly discuss small circular mRNA (circRNA) vaccines for cancer immunotherapy and the prevention of infectious diseases. Modification-free small circRNA vaccines are highly stable and sequence-defined with unique innate immunomodulatory mechanisms and sustained production of concatemeric antigens, resulting in robust and long-lasting adaptive immunity. Relative to several state-of-the-art modified mRNAs, nanocarrier-delivered circRNA vaccines elicited up to 10-fold antigen-specific T cells in mice, with superior T cell memory and vaccine safety. circRNA vaccines are widely applicable for tumor and viral (neo)antigens to elicit potent and long-lasting CD8+/CD4+ T cell responses in young or immunosenescent aged mice. Combining circRNA vaccines with immune checkpoint blockade (ICB) reduced tumor immunosuppression and eradicated multiple types of murine tumors, including ICB-resistant BrafV600E melanoma. Moreover, pulmonary delivery of influenza circRNA vaccines protected mice from influenza challenge. Overall, small circRNA vaccines are promising for versatile applications. Lastly, we will also briefly discuss our research in cGAS-STING- and ADAR1- related nucleic acid therapeutics and drug delivery systems for cancer and autoimmune diseases.

RNA Innovation Seminar: Susan Gottesman, NIH/NCI
2023-10-23 16:00 - 17:00
“Bacterial Small RNAs: Regulatory Circuits, On & Off Switches, & Quality Control”
Susan Gottesman, Ph.D.
Chief, Laboratory of Molecular Biology
NIH/NCI Distinguished Investigator

In-person: BSRB, ABC Seminar Rooms / hybrid link
Abstract: Bacteria use small regulatory RNAs (sRNAs) and the RNA chaperone Hfq to regulate mRNA translation and stability, akin to miRNAs and the RISC complex in eukaryotes. The approaches to defining bacterial sRNAs and their targets have dramatically improved since the screens that first identified many of them over 20 years ago. Current tools provide a global view of Hfq-binding RNAs that suggests increasingly interwoven regulatory networks, helping cell respond appropriately to stress and host interactions. On-switches for sRNAs are primarily at the level of transcription; when transcription ceases, most of the sRNAs are used stoichiometrically, being degraded as they are used, providing an effective Off-switch for sRNA regulation. We have used genetic screens to identify novel regulators of both Hfq and the sRNAs. One of these, HqbA, binds directly to the distal face of Hfq, and competes with weakly binding RNAs for association with Hfq, suggesting it is a new quality control regulator for Hfq. Data suggests that this is a bifunctional protein, directly regulating Hfq by protein-protein interaction and regulating other processes independently of Hfq. HqbA, along with other factors, help to ensure appropriate hierarchy of sRNA function.
Keywords: mRNA translation; RNAse E; Escherichia coli.

RNA Innovation Seminar: Irina Artsimovitch, Ohio State University
2023-11-06 16:00 - 17:00
“Locking Rho up”
Irina Artsimovitch, Ph.D.
Arts & Sciences Distinguished Professor
Department of Microbiology
The Ohio State University
In-person: BSRB, ABC seminar rooms / hybrid link
Abstract: Bacterial termination factor Rho co-transcriptionally surveils the nascent RNA and releases damaged and junk transcripts from RNA polymerase. During rapid growth, Rho maintains the transcriptome health, but how is Rho activity modulated during dormancy or stress, conditions prevalent in natural habitats? Rho is a hexameric RNA helicase that adopts active closed-ring and inactive open-ring states, and the interconversion between these states is thought to be a key checkpoint in Rho control. I will discuss two mechanisms by which ligands that bind at Rho subunit interfaces restrain ring dynamics. The Sm-like Rof protein binds at the extended RNA-binding site of Rho, occluding its RNA- and RNA polymerase-binding sites and locking the hexamer open. The stress alarmone (p)ppGpp binds to the ATP-binding site and stabilizes the open ring, triggering phase separation into inactive higher-order oligomers and extended filaments. These and other anti-termination mechanisms are expected to silence Rho under conditions when unrestrained termination would be lethal.
Keywords: transcription; termination; Rho helicase; stress response; phase separation

RNA Innovation Seminar: George Lisi, Brown University
2023-11-20 16:00 - 17:00
“The Invisible Dance of CRISPR-Cas9 through Molecular Space and Time”
George Lisi, Ph.D.
Thomas J. & Alice M. Tisch Assistant Professor
Department of Molecular Biology, Cell Biology & Biochemistry
Brown University

In-person: BSRB, ABC seminar rooms / hybrid link
Abstract: This talk will focus on long-range signaling in CRISPR-Cas9, a cutting-edge genome editing tool. The transformative potential of Cas9 as a precision therapeutic cannot be realized without an understanding of its interdomain communication and the mitigation of deleterious off-target cleavage, which is being characterized at the atomic level in the group. A series of vignettes will highlight NMR studies of Cas9 through a “divide-and-conquer” approach using engineered protein constructs and first demonstrate that multi-timescale motions in the catalytic nuclease of Cas9 propagates chemical information that regulates cleavage of double-stranded DNA. The talk will also highlight specificity-enhancing mutations in Cas9 that rewire its regulatory mechanism and RNA interactions at the molecular level to mitigate off-target DNA cleavage. Critical energetics of the mechanism will be discussed, including the importance of metal ions and the protonation state of the catalytic histidine, studied via catalytic pocket mutations that limit conformational sampling of the Cas9 active state. Lastly, insight from canonical Cas9s will be expanded to highly stable thermophiles that are more promising for genome engineering and offer tunable high-temperature DNA editing and RNA binding. The underlying chemistry and atomic level dynamics of Cas9 will be linked to its nucleic acid interactions and biological outcomes, hopefully opening new avenues for intuitive manipulation of its function and precision therapeutic properties.

RNA Innovation Seminar: Andy Berglund, University at Albany
2023-12-04 16:00 - 17:00
“Mis-splicing in repeat expansion diseases and development of potential therapeutics”
Andy Berglund, Ph.D.
Empire Professor of Innovation
Director of the RNA Institute
University at Albany

In-person: BSRB, ABC Seminar Rooms / hybrid link
Abstract: Repeat or microsatellite expansions are responsible for more than 50 human diseases. Myotonic dystrophy (DM), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxias (SCAs) are a few examples of repeat expansion diseases. RNA processing (pre-mRNA splicing) pathways are negatively impacted in these diseases with specific changes in pre-mRNA splicing proposed to lead to symptoms observed in affected individuals. Many of the projects in the lab combine biochemical, molecular, and genomic approaches with cellular and other model systems to understand the mechanisms through which these diseases alter pre-mRNA splicing. Through screening approaches, small molecules have been identified that reduce the levels of the repeat expansion RNAs and rescue mis-splicing in DM and SCA cell and animal models.
Keywords: Myotonic Dystrophy, Spinocerebellar Ataxias, Alternative Splicing and RNA Binding Proteins

RNA Innovation Seminar: Anthony Rosenzweig, University of Michigan
2024-01-22 16:00 - 17:00
“Noncoding RNA Targets in Heart Failure”
Anthony Rosenzweig, M.D.
Professor of Internal Medicine
Director of the MM Institute of Heart & Brain Health
University of Michigan

In-person: BSRB, ABC seminar rooms / hybrid link
Abstract: TBA

RNA Innovation Seminar: Sarah Woodson, Johns Hopkins University
2024-02-05 16:00 - 17:00
“How chaperones help RNAs choose the right partner”
Sarah Woodson, Ph.D.
T.C. Jenkins Professor of Biophysics
Johns Hopkins University

In-person: BSRB, ABC seminar rooms / hybrid link
Abstract: Non-coding RNAs must fold into specific structures to create the machinery for protein synthesis or to control gene expression. As nascent transcripts can form different base pairing interactions, finding the right partner can take time. RNA chaperone proteins increase the RNA dynamics, enabling the kinetic selection of optimal RNA interactions. How a DEAD-box helicase improves the fidelity of ribosome assembly and how Hfq increases the selectivity of small RNA regulation will be discussed.

RNA Innovation Seminar: Joan Steitz, Yale University
2024-02-19 16:00 - 17:00
“RNA-RNA Base Pairing: Key to unlocking the functions of many noncoding RNAs”
Joan Steitz, Ph.D.
Sterling Professor of Molecular Biophysics and Biochemistry
Yale University

In-person: BSRB, ABC seminar rooms / hybrid link
Abstract: Dr. Steitz’s talk will be primarily historical, with many examples of discoveries of RNA-RNA base pairing over her 50-year+ career being reviewed. At the end, she will mention her latest unpublished finding: how RNA-RNA-based pairing prevents neuronal death under stress conditions.

8th Annual RNA Symposium
2024-03-08 08:30 - 17:00
“Unmasking the Power of RNA: From Structure to Medicine”
Friday, March 8, 2024, 8:30 am – 5:00 pm
A. Alfred Taubman Biomedical Science Research Bldg, Kahn Auditorium
109 Zina Pitcher Pl, Ann Arbor, Michigan
For More Information and to Register, Click Here.

RNA Innovation Seminar: Evgeny Nudler, New York University
2024-03-18 16:00 - 17:00
“Transcription-driven DNA Repair”
Evgeny Nudler, Ph.D.
Julie Wilson Anderson Professor of Biochemistry
Investigator, Howard Hughes Medical Institute
Department of Biochemistry & Molecular Pharmacology
NYU Grossman School of Medicine

In-person: BSRB, ABC seminar rooms / hybrid link
Abstract: Using E. coli as a model system, we have developed new approaches to study damage recognition and processing in vivo for three major DNA repair pathways, nucleotide excision repair (NER), ribonucleotide excision repair (RER), and base excision repair (BER). Our recent findings let us to formulate a conceptually new model of global transcription-driven repair (TDR), in which RNA polymerase serves as the indispensable genome-wide DNA damage sensor and also delivery vehicle and platform for the assembly of specialized repair complexes in living cells. The model provides a framework for better understanding genotoxic stress response and genome instability in bacteria and beyond.
Keywords: DNA repair, transcription elongation, RNA polymerase, ppGpp, NER, BER, RER

RNA Innovation Seminar: Shuying Sun, Johns Hopkins University
2024-04-01 16:00 - 17:00
“RNA Metabolism in C9ORF72-linked neurodegenerative diseases ALS and FTD”
Shuying Sun, Ph.D.
Associate Professor, Department of Physiology
Brain Science Institute
Johns Hopkins University School of Medicine

In-person: BSRB, ABC seminar rooms / hybrid link
Abstract: We have a long-standing interest in RNA metabolism dysfunction and RNA-targeting therapy in neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The hexanucleotide GGGGCC repeat expansion in C9ORF72 is the most frequent genetic cause of both ALS and FTD. RNA-mediated gain of toxicity is critical for the pathogenesis. We employ multiple molecular approaches to understand the regulation of the repeat RNA processing, uncover genetic modifiers, and elucidate the influence on global RNA metabolism. We aim to understand the disease mechanisms and identify potential therapeutic targets for C9ORF72-ALS/FTD.

**CANCELED** RNA Innovation Seminar: Catherine Kaczorowski, University of Michigan
2024-05-06 16:00 - 17:00
**CANCELED**
Due to unforeseen circumstances, today’s RNA Innovation seminar featuring Dr. Catherine Kaczorowski has been canceled. Please be on the lookout for rescheduling information in the coming days
“Using Complex Genetics in Mice to Unlock the Secrets of Cognitive Resilience”
Catherine Kaczorowski, Ph.D.
Elinor Levine Professor of Dementia Research
Professor of Neurology
University of Michigan, Medical School
In-person: BSRB, ABC Seminar Room / hybrid link
Abstract: Alzheimer’s Disease, Systems Genetics, Resilience

RNA Innovation Seminar: Alexandra Piotrowski-Daspit, Internal Medicine
2024-06-03 16:00 - 17:00
“RNA: the delivery perspective”
Alexandra Piotrowski-Daspit, Ph.D.
Assistant Professor, Biomedical Engineering
Assistant Professor, Internal Medicine – Pulmonary & Critical Care Medicine Division
University of Michigan

In-person: BSRB, Kahn Auditorium / hybrid link
Abstract: The primary barrier for clinical translation of RNA therapeutics remains delivery to target tissues in vivo. Upon entering the body, delivery vehicles encounter extracellular and intracellular barriers. It is also unclear how carrier design features impact physiological interactions with biological systems, highlighting the need for studies that elucidate these structure-function relationships. In this seminar, I will describe our work on developing polymeric nanoparticles (NPs) to deliver therapeutic RNAs to a variety of tissues following local and systemic IV administration. We find that gene therapy can be significantly enhanced using a new class of polymeric vehicles consisting of poly(amine-co-ester) (PACE) polymers that are designed for safe and effective nucleic acid delivery. We have also developed tools to study nanomaterial-biology interactions in animal models, including a high-throughput quantitative microscopy-based platform to measure circulation half-life and biodistribution in vivo. This tool, alongside the development of novel polymeric carriers, can be used to study the structure-function relationships that guide the physiological fate of NPs in order to rationally design more effective delivery vehicles for RNA delivery.
Keywords: RNA therapeutics, in vivo delivery, polymeric nanoparticles (NPs), nanomaterial-biology interactions

David R. Walt, Ph.D. — Special Lecture and Open House Breakfast
2024-09-12 09:00 - 12:30 | Michigan League, 911 N University, Ann Arbor, MI, 48109, United States
The Center for RNA Biomedicine presents microwell array pioneer, David R. Walt, PH.D.

On Thursday, September 12, the Center for RNA Biomedicine will host life sciences industry expert David R. Walt, Ph.D. for a special lecture titled, “Why sensitivity matters for clinical diagnosis (see abstract below).”
Following the lecture, there will be an open house breakfast with opportunities to socialize with peers and connect with Dr. Walt.
Schedule — Thursday, September 12 | 9 a.m. – 12:30 p.m.
9 a.m. – 10:15 a.m. | David Walt, Ph.D. Lecture — Koessler Room, 3rd Floor, Michigan League
10:30 a.m. – 12:30 p.m. | Open House Breakfast with Dr. Walt — Henderson Room (directly across from Koessler), 3rd Floor, Michigan League
**A hybrid option is being offered via Zoom — click here to register.**
Whether in person or virtual, we hope you’ll join us for learning, coffee, and socializing with one of the top minds in fields of bio-inspired engineering, RNA-based clinical diagnosis, and life sciences startups.
Abstract and Speaker Info
Abstract:
A major challenge for many clinical diagnostic applications is the quantification of low-abundance proteins and other biomolecules in biological fluids. For example, traditional techniques, such as enzyme-linked immunosorbent assay (ELISA), can only measure several hundred proteins in human blood, which is limiting because there are thousands of proteins present at low concentrations that are of potential diagnostic utility. Single-molecule technologies allow for digital counting of individual protein molecules and have enabled 1000-fold increases in sensitivity over conventional protein detection methods. We have pioneered the development of these technologies that provide for multiplexed measurements with femtomolar sensitivities or below. I will discuss the technologies and describe their application to neurodegenerative disease, cancer, and infectious diseases.
About David R. Walt, Ph.D.:
David R. Walt is the Hansjörg Wyss Professor of Bioinspired Engineering at Harvard Medical School, Professor of Pathology at Brigham and Women’s Hospital and Harvard Medical School, Core Faculty Member of the Wyss Institute at Harvard University, Associate Member at the Broad Institute, and is a Howard Hughes Medical Institute Professor. His lab’s research focuses on creating and using novel technologies to solve unmet clinical diagnostics problems. Walt is the Scientific Founder of Illumina Inc., Quanterix Corp., and has co-founded multiple other life sciences startups including Ultivue, Inc., Arbor Biotechnologies, Sherlock Biosciences, Vizgen, Inc., and Protillion Biosciences. He has received numerous national and international awards and honors for his fundamental and applied work in the field of optical microwell arrays and single molecules including the 2023 National Academy of Engineering’s Fritz J. and Dolores H. Russ Prize and the 2021 Kabiller Prize in Nanoscience and Nanomedicine. He is a member of the U.S. National Academy of Engineering, the U.S. National Academy of Medicine, a Member of the American Philosophical Society, a Fellow of the American Academy of Arts and Sciences, a Fellow of the American Institute for Medical and Biological Engineering, a Fellow of the American Association for the Advancement of Science, a Fellow of the National Academy of Inventors, and is inducted in the US National Inventors Hall of Fame.

RNA Innovation Seminar: Gregor Neuert, Ph.D. — Vanderbilt University
2024-09-23 16:00 - 17:00 | BSRB – ABC Seminar rooms, 109 Zina Pitcher Pl, Ann Arbor, MI, 48109, United States
The University of Michigan Center for RNA Biomedicine Seminar Series is excited to host Gregor Neuert, Ph.D., for the first talk of the 2024 – 2025 RNA Innovation Seminar Series.

Gregor Neuert, Ph.D.
Associate Professor,
Molecular Physiology and Biophysics
Biomedical Engineering,
Pharmacology
Vanderbilt University

Date and Time: Monday, September 23 | 4 p.m.
In-person: Kahn Auditorium, BSRB
Virtual: The seminar will be available via Zoom for those unable to attend in person. Click here to register for the Zoom.
Talk Title: “Transcriptional stochasticity reveals multiple mechanisms of long non-coding RNA regulation”

Abstract:
Long noncoding RNAs (LncRNAs) are increasingly recognized as being involved in human physiology and diseases, but there is a lack of mechanistic understanding for the majority of lncRNAs. We comparatively tested proposed mechanisms of antisense lncRNA regulation at the X-chromosome Inactivation (XCI) locus. Our single-cell analyses argue against mechanisms that require the Xist or Tsix transcript to bind to each other. Intriguingly, we find that due to stochasticity in transcription, different mechanisms based on the act of transcription regulate Xist and Tsix at different levels of nascent transcription. At medium levels, RNA polymerases transcribe Xist and Tsix on each strand at the same transcription site and deposit significant amounts of the histone mark H3K36me3, which inhibits Xist. At high levels of nascent transcription, many RNA polymerases transcribe Xist or Tsix resulting in transcriptional interference. Therefore, lncRNA expression variability is not just a quirk of transcription but an important aspect of regulation that allows multiple mechanisms to be employed by the same gene locus within the same cell population.
Please visit the Neuert Lab for Quantitative Systems Biology website to learn more about Dr. Neuert and his work.

RNA Innovation Seminar: Joseph Yesselman, Ph.D. — University of Nebraska
2024-10-07 16:00 - 17:00 | BSRB – Kahn Auditorium
The University of Michigan Center for RNA Biomedicine Seminar Series will host Joseph Yesselman, Ph.D., as part of the 2024 – 2025 RNA Innovation Seminar Series.
Joseph Yesselman, Ph.D.
Assistant Professor, Chemistry
University of Nebraska

Date and Time: Monday, October 7 | 4 p.m.
In-person: Kahn Auditorium, BSRB
Hybrid Option: Click here to join the Zoom.

Talk Title: “High-throughput determination of RNA tertiary contact thermodynamics by quantitative DMS chemical mapping”
Abstract:
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 or require specialized instruments. Here, we introduce a new quantitative chemical mapping method (qMaPseq) to measure Mg2+-induced formation of tertiary contact thermodynamics in a high-throughput manner using standard biochemistry equipment. With qMaPseq, we measured the ΔG of 98 unique tetraloop/tetraloop receptor (TL/TLR) variants in a one-pot reaction. These results agree well with measurements from specialized instruments (R2=0.64). Furthermore, the DMS reactivity of the TL directly correlates to the stability of the contact (R2=0.68), the first direct evidence that a single DMS reactivity measurement reports on thermodynamics. Combined with structure prediction, DMS reactivity allowed the development of experimentally accurate 3D models of TLR mutants. These results demonstrate that qMaPseq is broadly accessible, high-throughput, and directly links DMS reactivity to thermodynamics.
Please visit the Yesselman Lab website to learn more about Dr. Yesselman and his work.

RNA Innovation Seminar: Laura Scott, Ph.D., University of Michigan School of Public Health
2024-10-21 16:00 - 17:00 | BSRB – Kahn Auditorium
“Regulation of RNA levels in muscle and adipose tissues by sex and genetic variants”
Laura Scott, Ph.D.
Research Professor, Biostatistics
University of Michigan School of Public Health
Research interests:
Dr. Scott uses a combination of bulk and single nucleus omic data – RNA expression, chromatin accessibility, metabolites and DNA methylation – to understand the cellular genetic regulatory landscape and to infer biological connections between genetic variation and disease risk.
Click here to read more about Dr. Scott and her work in a 2020 Faculty Spotlight article.
In-person: BSRB, Kahn Auditorium / hybrid link

Abstract:
Gene expression is regulated by multiple factors including genetic variation, sex, and cell type. I will describe differences by sex in human skeletal muscle cell type composition, cell type-level gene expression and chromatin accessibility, and bulk miRNA expression in 287 people. I will describe regulation of subcutaneous adipose gene expression by genetic variants in a meta-analysis of >2,200 people. These studies help to better understand transcription and post-transcriptional regulation of gene expression by sex and genetic regulation of gene expression.

RNA Innovation Seminar: Nils G. Walter, Ph.D., Co-Director, U-M Center for RNA Biomedicine
2024-11-04 16:00 - 17:00 | BSRB – Kahn Auditorium
“Single molecules come into focus: From bacterial riboswitches to mammalian cellular phase separation”
Nils G. Walter, Ph.D.
Co-Director,
U-M Center for RNA Biomedicine
Francis S Collins Collegiate Professor of Chemistry, Biophysics, and Biological Chemistry,
U-M LSA

Abstract:
At least 75% of the 3 billion base pairs of the human genome are transcribed into RNA, but the vast majority of these transcripts do not code for proteins but rather for “non-coding” RNAs (ncRNAs), many of which remain uncharacterized in terms of their structure and function. Currently, more than 80,000 unique ncRNAs have been identified in human cells alone, suggesting that for a long time we have underestimated the intricacies involved in human genome maintenance, processing, and regulation by neglecting this far-reaching “RNA World.” Nature and modern nanotechnology likewise employ nanoscale RNA machines that self-assemble into structures of complex architecture and functionality. Fluorescence microscopy offers a non-invasive tool to probe, dissect and ultimately control these nanoassemblies in real-time. In particular, single molecule fluorescence resonance energy transfer (smFRET) allows us to measure distances at the 2-8 nm scale, whereas complementary super-resolution localization techniques based on Gaussian fitting of imaged point spread functions (PSFs) measure distances in the 10 nm and longer range. Encapsulating the power of these recent technical advances, we have combined single-molecule and biochemical approaches to show that a central, adaptable RNA helix in the widespread manganese-sensing riboswitch functions analogous to a molecular fulcrum to integrate disparate signals for finely balanced bacterial gene expression control. We posit that many more examples of such intimate structural and kinetic coupling between RNA folding and gene expression remain to be discovered, leading to the exquisite regulatory control and kinetic proofreading enabling all life processes. On the more applied side, we are developing tools to study the liquid-liquid phase separation of RNA-protein granules involved in human pathologies.
Biography:
Nils G. Walter (photo by Michigan Photography) 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 co-directs the Center for RNA Biomedicine at Michigan, now developing a thrust in RNA Therapeutics. His research interests focus on gene regulation by noncoding RNAs through the lens of single molecule techniques and applications in drug discovery.
In-person: BSRB, Kahn Auditorium / hybrid link

Links to learn more about Nils Walter and his work:
Nils Walter’s Faculty Page
Nils Walter’s Lab Page
Nils Walter’s Wikipedia Page
