Center for RNA Biomedicine

RNA Innovation Seminar: Joan Steitz, Yale University
2024-02-19 16:00 - 17:00 (America/Detroit) | MI
“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 At the end, she will mention her latest unpublished finding: how RNA-RNA-based pairing prevents neuronal death under stress conditions.

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: 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: 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: 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: 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: 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: 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.

"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: 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.

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: 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.

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: 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: 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: 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: 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: 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: 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: Gal Haimovich, Weizmann Institute of Science
2023-02-13 12:00 - 13:00
“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: Carlos Cruchaga, Washington University in St Louis
2023-01-30 16:00 - 17:00
“Role of Circular RNA in Alzheimer’s Disease”
Carlos Cruchaga, Ph.D.
Director, NeuroGenomics and Informatics Center
Washington University in St Louis
In-person: BSRB, ABC seminar rooms / hybrid link
Short Bio: Dr. Cruchaga is a human genomicist with expertise in multiomics, informatics, and neurodegeneration. He completed his PhD in Biochemistry & Molecular Biology in 2005 at the University of Navarra in Spain. During his first postdoc with Dr. Pastor he conducted statistical human genetics studies focused on Alzheimer’s disease (AD) and Parkinson’s disease (PD). He then moved to Dr. Goate’s Lab to complete his training in quantitative human genomics. Dr Cruchaga established his laboratory at Washington University in 2011 to study the genetic architecture of neurodegenerative diseases. His interests are focused on using human genomic and other -omis data (proteomics, metabolomics, & lipidomics) to identify and understand the biological processes that lead to AD, PD, frontotemporal dementia, and other neurodegenerative processes. He is the founding director of the NeuroGenomics and Informatics Center at Washington University.
Abstract: Circular RNAs (circRNAs) are a class of RNAs highly expressed in the nervous system and enriched in synaptoneurosomes. In Alzheimer Disease, synapse lost is one of the events implicated on disease. circRNA are form by back-splicing (head-to-tail splicing), and where first described in eukaryotic cells and other studies suggested that synapse could be enriched for circRNA. Based on we hypothesized that specific circRNA would be differentially expressed in AD cases compared to controls and that those effects could be detected early in the disease. We optimized and validated a novel analyses pipeline for circular RNAs (circRNA). We performed a three-stage study design to robustly identify circRNA associated with AD and AD-related phenotypes. Additional analyses were performed to demonstrate that the expression of circRNA were independent of the lineal form as well as the cell proportion that can confound results. Co-expression analyses of all the circRNA together with the lineal forms and found that circRNA, including those that were differentially expressed in Alzheimer disease compared to controls co-expressed with known causal Alzheimer genes, such as APP and PSEN1, indicating that some circRNA are also part of the causal pathway. We also demonstrated that cirRNAs brain expression explained more about Alzheimer clinical manifestations that the number of APOε4 alleles, suggesting that could be used as a potential biomarker for Alzheimer disease. In summary, we demonstrated for the first time that brain circular RNAs (circRNA) are part of the pathogenic events that lead to Alzheimer’s disease

RNA Innovation Seminar: Karen Mohlke, UNC
2023-01-09 16:00 - 17:00
“Genetic Variant Effects on Adipose Gene Expression and Their Role in Cardiometabolic Traits.”
Karen Mohlke, Ph.D.
Professor and Associate Chair for Research
Oliver Smithies Investigator
Department of Genetics, University of North Carolina
In-person: BSRB, ABC seminar rooms / hybrid link
Abstract: Noncoding genetic variants can affect common diseases and related quantitative traits. Variants may affect the expression levels of transcripts and alternatively-spliced isoforms, dependent on cell context. I will describe genetic variants associated with adipose tissue gene expression level in >2,200 people and their putative roles in cardiometabolic disease traits. Similarly, I will implicate variants associated with splice junction usage in disease risk. Finally, based on chromatin accessibility during adipocyte differentiation, I will show genetic regulatory effects that depend on cell context. Together, these studies help identify regulatory mechanisms for common diseases.
Keywords: Transcriptome, expression quantitative trait loci (eQTL), splice QTL (sQTL), genome-wide association study (GWAS), chromatin accessibility, epigenome, adipose tissue, adipocyte.

RNA Innovation Seminar: Hayley McLoughlin, Neurology
2022-12-19 16:00 - 17:00
“Antisense Oligonucleotides for Ataxia”
Hayley McLoughlin, Ph.D.
Assistant Professor of Neurology
Assistant Professor of Human Genetics
University of Michigan

In-person: BSRB, ABC seminar rooms / hybrid link
Abstract: Her talk will cover recent advances in antisense oligonucleotide (ASO) therapy with a particular emphasis towards their mechanistic and therapeutic applications in Ataxia. She will specifically discuss ASO approaches in the most common dominantly inherited ataxia, Spinocerebellar ataxia type (SCA3). SCA3 is one of nine polyglutamine expansion diseases and is caused by a gain-of-function repeat expansion in the disease gene, ATXN3. To date, there is no effective treatment for this relentlessly progressive and fatal neurodegenerative disease. Throughout her postdoctoral training in Dr. Paulson’s lab and into her independent research career, she has assessed the efficacy and tolerability of anti-ATXN3 ASO gene silencing therapy in SCA3 mouse models in collaboration with Ionis Pharmaceuticals. Published in successive cross-sectional (PMC5415970) and longitudinal studies (PMC6119475), they defined the first evidence of a gene therapy mitigating both pathological and behavioral disease phenotypes in the SCA3 mouse, which overexpresses the full-length human disease gene. These anti-ATXN3 ASOs are currently begin assessed in SCA3 human subjects through a Phase 1 clinical trial driven by Biogen for pharmacokinetics and safety (ClinicalTrials.gov Identifier: NCT05160558).

RNA Therapeutics Seminar: Melissa Moore, CSO, Moderna Therapeutics, Emerita
2022-12-19 12:00 - 13:00
“The Science Behind mRNA Medicines: COVID-19 Vaccines and Beyond”
Melissa J. Moore, Ph.D.
Chief Scientific Officer, Moderna Therapeutics, Emerita
In-person: BSRB, Kahn Auditorium and hybrid. Here is the link for the seminar video.
Dr. Moore will be awarded an honorary degree at the University of Michigan Ann Arbor campus’ 2022 Winter Commencement and give this scientific talk to our RNA community.

Biography: From 2016-2021, Dr. Moore led the early-stage research teams developing Moderna’s platform technologies in mRNA design and delivery. These technologies were foundational for Moderna’s ability to rapidly create a highly effective vaccine against SARS-CoV-2. As CSO, Emerita, she now focuses on explaining the science behind mRNA medicines. During her 23 years as faculty member, first at Brandeis University (1994-2007) and then at the University of Massachusetts Medical School (2007-2016), her research encompassed a broad array of topics related to the roles of RNA and RNA-protein (RNP) complexes in gene expression, and touched on many human diseases including cancer, neurodegeneration and preeclampsia. A long-time Investigator at the Howard Hughes Medical Institute (HHMI), Dr. Moore is an elected member of the National Academy of Sciences (2017), a Fellow of the American Academy of Arts and Sciences (2019), and recipient of the RNA Society Lifetime Achievement Award (2021).
Dr. Moore holds a B.S. in Chemistry and Biology from the College of William and Mary, and a Ph.D. in Biological Chemistry from MIT, where she specialized in enzymology under Prof. Christopher T. Walsh. She bean working on RNA metabolism during her postdoctoral training with Philip A. Sharp at MIT. Her passions include educating the public about the coming age of nucleic acid medicines and increasing Diversity, Equality and Inclusion (DEI) at all levels of the biotechnology workforce.

RNA Innovation Seminar: Francesca Luca, Wayne State University
2022-12-05 16:00 - 17:00
“Genetic, environmental, and developmental factors in immune cell gene expression and asthma”
Francesca Luca, Ph.D.
Professor
Center for Molecular Medicine and Genetics
Wayne State University

In-person: BSRB, ABC seminar rooms / hybrid link
Abstract: Asthma is an immunological disorder with genetic and environmental components. In the last ten years we have been studying genetic and environmental factors that contribute to asthma severity in children living in the metropolitan Detroit area, as part of the NHLBI funded project: Asthma in the Lives of Families Today (ALOFT). We have performed bulk and single cell RNA-sequency in this cohort and uncovered psychosocial and genetic factors associated with asthma. I will present our findings on the dynamic genetic regulation of gene expression in response to immunomodulators and during pubertal development. I will also discuss the importance of considering environmental and developmental contexts when using molecular data to study the genetic risk of asthma and other complex traits.
Keywords: Gene expression, gene-environment interactions, eQTL, asthma, single cell genomics

RNA Innovation Seminar: Jeremy Schroeder, Biological Chemistry
2022-11-21 16:00 - 17:00
“RNA:DNA hybrids cause genome instability through nucleobase deamination, genomic rearrangements, and induction of the DNA damage response”
Jeremy Schroeder, Ph.D.
Research Investigator
Biological Chemistry
University of Michigan

In-person: BSRB, ABC seminar rooms / hybrid link
Abstract: The overall impacts of naturally occurring RNA:DNA hybrids on genome integrity, and the relative contributions of ribonucleases H to mitigating the negative effects of these hybrids, remain unknown. Here, we use the model bacterium Bacillus subtilis to investigate the contribution of RNases HII (RnhB) and HIII (RnhC) to hybrid removal, DNA replication, and mutagenesis genome-wide. Deletion of either rnhB or rnhC alters RNA:DNA hybrid formation, but with distinct patterns of mutagenesis and hybrid accumulation. For ΔrnhB, hybrids form preferentially in genes transcribed co-directionally with DNA replication. For ΔrnhC, hybrids accumulate in all genes regardless of their orientation, and DNA replication is disrupted leading to transversions and structural variation. We find that base deamination in the displaced strand of an R-loop leads to transition mutations in coding sequences, independent of gene orientation. Our results resolve the outstanding question of how hybrids in native genomic contexts interact with replication to cause mutagenesis.

RNA Therapeutics Seminar: John Cooke, M.D., Ph.D., Medical Director, Center for RNA Therapeutics, Houston Methodist
2022-10-17 16:00 - 17:00
“The Democratization of RNA Therapeutics”
John Cooke, M.D., Ph.D.
Joseph C. “Rusty” Walter and Carole Walter Looke Presidential Distinguished Chair in Cardiovascular Disease Research, Department of Cardiovascular Sciences
Chair, Department of Cardiovascular Sciences
Professor of Cardiovascular Sciences, Academic Institute
Full Member, Research Institute
Director, Center for Cardiovascular Regeneration
Medical Director, Center for RNA Therapeutics
Houston Methodist

Flyer in PDF
In-person: BSRB, ABC room with zoom option
Abstract: mRNA therapeutics is a disruptive therapeutic technology, as small biotech startups, as well as academic groups, can rapidly develop new and personalized mRNA constructs. In the Texas Medica Center, we have established a Center for RNA Therapeutics that comprises faculty innovators, as well as a translational assembly line to bring great RNA ideas to life. Academic groups and small companies work with us as we innovate, design, synthesize, purify, encapsulate and test mRNA therapies. In addition to providing pre-clinical GLP testing, we have established cGMP-compliant manufacturing capability and quality control methods to support pre-clinical GLP studies and phase I clinical trials; and have a first-in-man phase 1 clinical trial unit. To support phase II and phase III trials, and commercialization, we have licensed our proprietary manufacturing processes to VGXI Inc, a local company with large-batch manufacturing capabilities for DNA-based gene therapies. With this collaboration, we have built a seamless transition for academic groups and small companies to go from pre-clinical development and first-in-man clinical trials supported by our hospital-based program, to late-stage clinical trials and commercialization supported by our industry partner VGXI, Inc.

Flyer in PDF

RNA Innovation Seminar: Polly Hsu, Michigan State University
2022-10-10 16:00 - 17:00
“Roadblocks on mRNAs? Gene Expression Regulation by Upstream Open Reading Frames in Plants”
Polly Hsu, Ph.D.
Assistant Professor
Biochemistry and Molecular Biology
Michigan State University

Flyer in PDF
In-person: BSRB, ABC seminar rooms / hybrid link
Keywords: translation, uORFs, nonsense-mediated decay
Abstract: 30-70% of mRNAs in humans, mice and plants contain short ORFs, called upstream ORFs (uORFs), in their 5’ leader sequences. The translation of uORFs is expected to repress the protein synthesis of their downstream main ORF (mORF) and to trigger mRNA degradation, presumably through nonsense-mediated decay (NMD). I will share our current progress investigating the global and gene-specific mechanisms by which uORFs regulate gene expression in Arabidopsis and tomato. I will discuss 1) different classes of uORFs revealed by Ribo-seq, 2) the roles of uORFs on transcription factor and protein kinase genes, 3) the mRNA stability of uORF-containing genes, and 4) cellular regulatory mechanisms to include or avoid uORFs on mRNA sequences.

RNA Innovation Seminar: David Shechner, University of Washington
2022-09-26 16:00 - 17:00
“Meet the neighbors: A universal technology for probing RNA-interactions and RNA-scaffolded subcellular compartments in situ”
David Shechner Ph.D.
Assistant Professor of Pharmacology
University of Washington

Flyer in PDF
In-person: BSRB, ABC seminar rooms / hybrid link
Keywords: RNA, proximity-biotinylation, subcellular architecture, nuclear architecture, spatial biology, biomolecular condensates, interactomics, nucleolus, Xist.

Abstract: In the context of the living cell, very little RNA is naked. RNA molecules form complex, dynamic networks of molecular interactions that underlie a host of biochemical functions, and which are central to organizing subcellular compartmentalization. In humans, for example, RNAs are key determinants of chromatin folding, and they nucleate and scaffold a host of biomolecular condensates that collectively control cellular metabolic, epigenetic, and stress-signaling pathways. But, characterizing these structures—identifying the biomolecules within an RNA’s subcellular microenvironment—remains technically cumbersome.
To address this challenge, I introduce oligonucleotide-mediated proximity-interactome mapping (O-MAP), a straightforward and flexible method for identifying the proteins, RNAs, and genomic loci near a target RNA, within its native cellular context. O-MAP uses programmable oligonucleotide probes to deliver proximity-biotinylating enzymes to a target RNA. These enzymes then pervasively label all nearby (~20 nm) molecules, enabling their enrichment by streptavidin pulldown. O-MAP induces exceptionally precise RNA-targeted biotinylation, and its modular design enables straightforward validation of probe pools and real-space optimization of the biotinylation radius, thus overcoming key technical challenges for the field. Moreover, O-MAP can be readily ported across different target RNAs and specimen types, including patient-derived organoids and tissue samples. And, O-MAP achieves this without complex cell-line engineering, using only off-the-shelf parts and standard manipulations.
Using a small cohort of model RNAs, we have developed a robust O-MAP toolkit for proteomic (O-MAP-MS), transcriptomic (O-MAP-Seq) and genome interaction (O-MAP-ChIP) discovery. O-MAP of the 47S-pre-rRNA—the long noncoding RNA that scaffolds the nucleolus—enabled a comprehensive “multi-omic” analysis of this subnuclear structure, and revealed hundreds of novel nucleolar protein-, RNA-, and chromatin interactions. O-MAP of XIST—the master regulator of X-chromosome inactivation—revealed novel RNAs that may play a role in this process, and unanticipated interactions between XIST and other chromatin-regulatory RNAs. Finally, targeting O-MAP to introns within a key cardiac developmental gene enabled unprecedented molecular dissection of a subnuclear compartment that would be impossible to purify biochemically.
Given these results, we believe that O-MAP will be a powerful tool for elucidating the mechanisms by which RNA molecules drive subcellular compartmentalization in time and space, with particular impact on our understanding of nuclear architecture. Moreover, with O-MAP’s precision, flexibility, and ease, we anticipate its broad use in studying countless other RNA phenomena throughout biology, and as a clinical diagnostic- and discovery tool.

RNA Innovation Seminar: Zhipeng Lu, USC
2022-09-12 16:00 - 17:00
“RNA Structures, Interactions and Modifications”
Zhipeng Lu (鲁志鹏), Ph.D.
Assistant Professor
Pharmacology and Pharmaceutical Sciences
University of Southern California

Flyer in PDF
In-person: BSRB, ABC seminar rooms / hybrid link
Abstract: RNA in living cells are in constant motion, form dynamic structures, and interact with many molecules, including other RNAs. Direct determination of RNA structures and interactions in vivo is essential to understanding their functions, but has been challenging in the past. We developed a number of novel chemical and computational tools to capture the 2D and 3D RNA structurome and interactome in cells, providing a comprehensive view of RNA conformations that underlie their roles in gene regulation and human diseases. Applications of these methods revealed new mechanisms in lncRNA functions, RNA modifications and splicing regulation.
