Center for RNA Biomedicine

RNA Faculty Candidate Seminar: Paul Donlin-Asp, Max Planck Institute for Brain Research
2021-12-13 16:00 - 17:00 (America/Detroit)
“Resolving the localisation and dynamics of mRNA and protein synthesis within neurons”
Paul Donlin-Asp, Ph.D.
Postdoctoral Researcher
Department of Synaptic Plasticity
Max Planck Institute for Brain Research

Flyer in PDF
Co-Host: The Department of Molecular, Cellular, and Developmental Biology
Hybrid Seminar:
In-person: Biomedical Science Research Building (BSRB), ABC Seminar rooms
Zoom: https://umich.zoom.us/webinar/register/WN_tZjYxppSQwaDVTYIuC0jkw
Keywords: mRNA dynamics, local protein synthesis, neurons, neuronal cell biology, synaptic plasticity, in vivo imaging
In-person event COVID guidelines

RNA Collaborative Seminar Series // Host: Harvard Medical School Initiative for RNA Medicine
2021-12-15 16:00 - 17:00
For the seminar details, visit: https://www.rnasociety.org/rna-collaborative-seminar-series

RNA Faculty Candidate Seminar: Dr. Alisha 'Jonesy' Jones, Institute of Structural Biology, Helmholtz Zentrum Munich
2021-12-20 16:00 - 17:00
“Modulation of the MALT1 pre-mRNA structure by hnRNP proteins regulates T cell activation”
Dr. Alisha ‘Jonesy’ Jones
Postdoctoral Researcher
Institute of Structural Biology
Helmholtz Zentrum Munich

Flyer in PDF
Co-Hosts: The Center for RNA Biomedicine, Department of Biological Chemistry, and the Program in Biophysics
Hybrid Seminar:
In-person: Biomedical Science Research Buliding (BSRB), ABC Seminar rooms
Zoom: https://umich.zoom.us/webinar/register/WN_3yrQ47UuTKKuzigbe38Sww
Keywords: pre-mRNA, hnRNP, NMR, SHAPE, structure
Abstract: Alternative splicing is controlled by differential binding of trans-acting RNA binding proteins (RBPs) to cis-regulatory pre-mRNA elements. How pre-mRNA secondary structure affects recognition by RBPs and determines alternative exon usage is poorly understood. The MALT1 paracaspase is a key component of signaling pathways that mediate innate and adaptive immune responses. Alternative splicing of MALT1 exon7 is critical for controlling optimal T cell activation. Here, we demonstrate that MALT1 pre-mRNA splicing depends on RNA structural elements that shield the splice sites of the alternatively spliced exon7. The RBPs hnRNP U and hnRNP L bind comparably and competitively to identical stem-loop RNA structures flanking the 5’ and 3’ splice sites of MALT1 exon7. While hnRNP U stabilizes RNA stem-loop conformations that maintain exon7 skipping, hnRNP L destabilizes these RNA elements to facilitate recruitment of the essential splicing factor U2AF2 to promote exon7 inclusion. This work represents a paradigm for the control of splice site selection by differential RBP binding and modulation of pre-mRNA structure.
In-person event COVID guidelines

RNA Faculty Candidate Seminar: Rachel Niederer, Yale School of Medicine
2022-01-10 16:00 - 17:00
“Uncovering novel translational control elements within 5′ UTRs”
Rachel Niederer, Ph.D.
Postdoctoral Researcher
Yale School of Medicine

Co-Hosts: The Center for RNA Biomedicine, Department of Biological Chemistry, and the Department of Human Genetics
Hybrid Seminar:
In-person: Biomedical Science Research Buliding (BSRB), ABC Seminar rooms
Zoom: https://umich.zoom.us/webinar/register/WN_qg4fyCUbQZyVu0oGrBLmWQ
Abstract: Translational control of gene expression plays an essential role during development, response to stress and a wide range of cellular processes. However, the key mRNA features that distinguish efficiently translated from poorly translated mRNAs remain largely unknown. This talk will describe the development of direct analysis of ribosome targeting (DART) and its use both in discovering novel regulatory elements within 5′ untranslated regions (5′ UTRs) as well as revealing unexpected behaviors from features that were previously thought to be well understood.
In-person event COVID guidelines
Flyer in PDF

RNA Faculty Candidate Seminar: Jailson (Jay) Brito Querido, MRC Laboratory of Molecular Biology
2022-01-31 16:00 - 17:00
“The scanning mechanism of mRNA translation initiation in humans”
Jailson (Jay) Brito Querido, Ph.D.
Postdoctoral Scientist
MRC Laboratory of Molecular Biology
Cambridge, UK

Co-Hosts: The Center for RNA Biomedicine, Department of Biological Chemistry, and the Program in Biophysics
Hybrid Seminar:
In-person: Biomedical Science Research Building (BSRB), ABC Seminar rooms
Zoom: https://umich.zoom.us/webinar/register/WN_pcS-fWIdSS-hDnKzoRhXeg
Keywords: mRNA, translation, ribosome, helicase
Abstract: Decoding the genetic information into protein is fundamental for all kingdoms of life. It requires precise mechanisms to transcribe the DNA into mRNA, which then can be translated by the ribosome to produce proteins. Translation initiation of eukaryotic mRNAs is a dynamic process regulated by over a dozen protein eukaryotic initiation factors (eIFs). This process starts with the binding of eukaryotic initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex of eIF2–GTP–tRNAiMet (TC) to the 40S small ribosomal subunit, forming the 43S preinitiation complex (43S PIC). Once assembled, the 43S PIC is recruited to the 5′ untranslated region (UTR) of mRNA by the multifactor cap-binding complex eIF4F, forming the 48S initiation complex (48S). The 48S then scans along the 5′ UTR mRNA to locate a start codon. The eIF4F binding site in the 48S and how mRNA is inserted into the mRNA channel in the 40S small ribosomal subunit remained unknown. To gain insights into the molecular mechanism underlining the assembly of the 48S, we used cryo-electron microscopy to determine the structure of a reconstituted human 48S. The structure sheds light on the early events of translation initiation complex assembly, including how eIF4F interacts with the 43S during the scanning process.
In-person COVID Events Policy

RNA Faculty Candidate Seminar: Margaret (Maggie) Rodgers, Johns Hopkins University
2022-02-14 16:00 - 17:00
“Mechanisms of co-transcriptional ribonucleoprotein assembly”
Margaret (Maggie) Rodgers, Ph.D.
Postdoctoral Researcher
Johns Hopkins University

Co-Hosts: The Center for RNA Biomedicine, Department of Biological Chemistry, and the Program in Biophysics
Hybrid Seminar:
In-person: Biomedical Science Research Buliding (BSRB), ABC Seminar rooms
Zoom: https://umich.zoom.us/webinar/register/WN_Icqg8jRbQNGCBEFkj_u5Gw
Keywords: RNA, RNP, ribosome assembly, transcription, single-molecule fluorescence
Seminar flyer in PDF
In-person event COVID guidelines

Seminar: John Prensner, MD, PhD
2022-02-28 16:00 - 17:00
“Translating the cancer genome: dark matter proteins”
John Prensner, M.D., Ph.D.
Physician, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Instructor of Pediatrics, Harvard Medical School

Co-Hosts: The Center for RNA Biomedicine, Department of Computational Medicine & Bioinformatics, and Department of Pediatric Oncology
Hybrid Seminar:
In-person: Biomedical Science Research Building (BSRB), ABC Seminar rooms
Zoom: https://umich.zoom.us/webinar/register/WN_bC6oy6VZTLy3ke4iMS2sKQ
Keywords: cancer, ribosome profiling, functional genomics, gene discovery
Abstract: Although genomic analyses predict many non-canonical open reading frames (ORFs) in the human genome, it is unclear whether they encode biologically active proteins in diseases such as cancer. Here, we have developed functional genomics platforms to systematically interrogate non-canonical ORFs identified in ribosome profiling data. Using CRISPR loss-of-function screens in numerous human cancer models, we define the frequency with which ORFs contribute to cell essentiality phenotypes. We further constructed large-scale ORF plasmid libraries to assess their capacity to encode a protein and induce cancer cell transcriptional changes. We pursued focused investigation of several uncharacterized protein-coding loci, defining roles for the lncRNA-ORF GREP1 in breast cancer and the ASNSD1 upstream ORF (uORF) in medulloblastoma. Lastly, we have assembled a pathway to bring such ORF candidates into the mainstream of biological research via an international consortium of gene database stakeholders. Together, this work establishes non-canonical ORFs as critical mediators of cancer cell biology, suggests their potential promise as therapeutic targets in cancer, and outlines a path forward for dissemination of these ORFs amongst the global research community.
In-person COVID Events Policy

RNA Therapeutics Seminar, Michelle Hastings, Rosalind Franklin University
2022-03-21 15:00 - 16:00
Inaugural RNA Therapeutics Seminar
Michelle Hastings, Ph.D.
Professor, Cell Biology and Anatomy; Director, Center for Genetic Diseases
Rosalind Franklin University of Medicine and Science

This is an internal U-M event:
In-person: Palmer Commons, Forum Hall
Zoom: https://umich.zoom.us/webinar/register/WN_mUj40sudTwmI6hXANnlJEg
Keywords: pre-mRNA splicing, Antisense oligonucleotides, Usher syndrome, Batten Disease, lysosomal storage diseases
Seminar flyer in PDF
In-person COVID Events Policy

6th Annual RNA Symposium
2022-03-25 08:30 - 16:00
Featured keynote speakers
Chris Burge, MIT
Michelle Hastings, Rosalind Franklin University of Medicine and Science
John Rinn, University of Colorado-Boulder
Gisela Storz, NIH
Jack Szostak, University of Chicago
For more details, visit: https://rna.umich.edu/2022-symposium/

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RNA Innovation Seminar: Wendy Gilbert, Ph.D.
2022-03-28 16:00 - 17:00
“Marvelous U: Canonical and non-canonical functions of uridine modifying enzymes in health and disease”
Wendy Gilbert, Ph.D.
Associate Professor of Molecular Biophysics and Biochemistry
Yale School of Medicine
Flyer in PDF

Hybrid Seminar
In-person: BSRB, ABC Seminar Rooms
Zoom: https://umich.zoom.us/webinar/register/WN_P6PEipcsRPmG7cAL104K-Q
Keywords:
RNA modifications, RNA processing, RNA folding, pre-mRNA, tRNA, translation, cancer
Abstract:
RNA modifications are essential for human health—too much or too little leads to serious illnesses ranging from neurodevelopmental disorders to cancer. We are working to uncover the RNA targets of RNA modifying enzymes that are dysregulated in disease and to understand their molecular and organismal roles. Recent advances in detecting the modified nucleosides pseudouridine and dihydrouridine reveal complex landscapes that include pre-messenger RNA and diverse classes of noncoding RNA in yeast and human cells. I will give an update on our progress towards answering three questions: How are specific RNA sites selected for modification and how is this process regulated? What are the molecular consequences of mRNA and non-coding RNA modifications? How do specific defects in RNA metabolism result in organismal phenotypes, including disease?

RNA Innovation Seminar: Silvi Rouskin, Ph.D.
2022-04-11 16:00 - 17:00
“Alternative structures of the SARS-CoV-2 RNA genome control gene expression and offer therapeutic strategies”
Silvi Rouskin, Ph.D.
Assistant Professor
Harvard Medical School

Virtual Seminar via Zoom: https://umich.zoom.us/webinar/register/WN_zi3UlKucR6G51hEA_33Exg
Keywords:
TBA
Abstract:
TBA

RNA Innovation Seminar: Paul Magwene, Ph.D., Duke University
2022-04-18 12:00 - 13:00
“Signaling Pathway Variation and Evolutionary Hotspots in the Fungi”
Paul Magwene, Ph.D.
Professor of Biology
Director, Computational Biology & Bioinformatics (CBB)
Duke University

PDF Flier
Hybrid Seminar
In-person: BSRB, ABC Seminar Rooms
Zoom: https://umich.zoom.us/webinar/register/WN_7wk1SlRdQ_e04VnwcjVV7g
Keywords:
population genomics, statistical genetics, gene networks, microbial pathogenesis
Abstract:
Evolutionarily conserved signal transduction pathways, such as Ras-cAMP-PKA, calcineurin, and TOR signaling, are primary regulators of stress responses and morphogenetic processes across the fungal tree of life. From an evolutionary perspective, these pathways are expected to be under relatively strong stabilizing selection, as loss-of-function mutations (LoF) in these pathways typically lead to reduced growth rates and increased sensitivity to environmental stresses. We have carried out comparative population genomic analyses of signaling pathway LoF alleles for multiple fungal species, and find that several pathways exhibit unusually high frequencies of naturally occurring putative LoF alleles. We discuss the implications of this finding for the evolutionary lability of signaling pathways in the fungi, and combine information on loss-of-function alleles with related evidence from QTL mapping and experimental evolution studies to identify pathways that may act as “evolutionary hotspots” for adaptation to novel environments.

RNA Innovation Seminar: Sika Zheng, UC Riverside, School of Medicine
2022-05-09 16:00 - 17:00
“Unexpected determinants of neuronal identity and properties: the curious cases of PTBP1, PTBP2, and neuronal splicing”
Sika Zheng, Ph.D.
Associate Professor, Director of Center for RNA Biology and Medicine
UC Riverside, School of Medicine

Flyer in PDF

Virtual Seminar
Zoom: https://umich.zoom.us/webinar/register/WN_dltbxWdHQ5KrC3rTl4hqLQ
Abstract:
Alternative splicing is the major contributor to transcriptome diversity, but splicing is noisy and to what extend alternative splicing regulation is indispensable for biolgical processes has been controversial. Our studies have revealed the regulation and function of neural-specific splicing in shaping neuronal identity and estalishing neurons’ two unique attributes: 1. Axonogenesis (Only neurons but no other cell types have one and single axon); 2. Neuronal longevity (Neurons are the most long-lived cell types). We show that obtaining these neuronal features is coordinated by RNA binding proteins PTBP1 and PTBP2, while PTBP1 was suggested by others to be a reprogramming factor of neuronal fate. I will discuss the regulatory mechanism of neural specific splicing underlying neurogensis and maturation.
References:
Zhang M, Ergin V, Lin L, Stork C, Chen L, Zheng S. Neuron. 2019 Feb 20;101(4):690-706.e10.
Ergin V, Zheng S. J Mol Biol. 2020 Jun 26;432(14):4154-4166.
Zheng S. Wiley Interdiscip Rev RNA. 2020 Jul;11(4):e1585.
Lin L, Zhang M, Stoilov P, Chen L, Zheng S. Neuron. 2020 Sep 23;107(6):1180-1196.e8.
Vuong J, Ergin V, Zheng S. Nature Communications (accepted)

RNA Innovation Seminar: Daniel O’Reilly
2022-05-16 16:00 - 17:00
“An Academic Approach to Oligonucleotide Therapeutics”
Daniel O’Reilly Ph.D., MRSC
Post-Doctoral Associate
Khvorova Lab
RNA Therapeutics Institute
University of Massachusetts Medical School
Flyer in PDF

HYBRID SEMINAR:
In-person: BSRC, ABC seminar rooms
Zoom: https://umich.zoom.us/webinar/register/WN_dM1a1aKVTM2KfwiieutOWg
Keywords: Oligonucleotides, Chemical Modifications, RNA, Huntington’s Disease
Abstract: Nucleic acids (NA) are becoming the third major pillar of therapeutic modalities on par with small molecules and biologics. The diversity of NA molecular mechanisms, ranging from vaccines, antisense, short interfering RNA (siRNAs), and guide RNA for CRISPR gene editing systems, enable impact on most aspects of cellular biology and thus human medicine. The foundation behind the recent oligonucleotides’ clinical success is fundamental chemical innovations in RNA stability, delivery, and synthesis.
Oligonucleotides are informational drugs; thus, if chemical architectures supporting safe and efficient delivery to the tissue of interest are achieved, they can be easily reprogrammed to modulate any gene expression on demand, creating an opportunity for academic institutions to drive therapeutic innovation. However, the process is limited by access to oligonucleotide chemistry and synthetic expertise.
In the first half of the talk, I will share the experience of building and running Nucleic Acid Chemistry Center in a context of a large academic institution. The NACC provides access to therapeutic quality screening leads and large manufacturing of preclinical compounds for the academic community. The impact of the NACC and chemical innovation will be discussed in the context of two significant projects. First, I will discuss the systematic structure-activity relationship study of chemical modifications to modulate RISC loading and cleavage. Screening 1200 siRNA variants allow for defining the chemical and thermodynamic rules for RISC assembly.

RNA Innovation Seminar: Analisa DiFeo & Bambarendage (Pini) Perera
2022-05-23 16:00 - 17:00
HYBRID SEMINAR:
In-person: BSRC, ABC seminar rooms
Livestream: https://umich.zoom.us/webinar/register/WN_mXMOsCvlQrSyuJQO0_EnWw

“A miRNA-mediated approach to dissect the complexity of cancer progression and identify anti-cancer drugs”
Analisa DiFeo, Ph.D.
Associate Professor
Pathology and Ob/Gyn
Michigan Medicine
Abstract: High grade serous carcinoma (HGSC) the most common type of “ovarian” cancer is one of the deadliest cancers diagnosed in women. One of the primary drivers for the high mortality rate associated with HGSC is tumor recurrence and chemoresistance. Thus, there is a critical need to identify the genetic drivers of tumor development and recurrence to improve therapeutic strategies. In this proposal, we provide extensive evidence for the clinical and biological importance of miR-181a, which is amplified in a large majority of HGSC patients, correlates with poor overall survival, and induces epithelial to mesenchymal transition (EMT), metastasis, drug resistance, and stem-like cell properties. Remarkably, this correlation between miR-181a with clinical outcome and recurrence has also been shown in numerous other cancers. Notably, miR-181a expression in HGSC tumors offered stronger prognostic value than established clinical biomarkers. Furthermore, analysis of >10,000 tumors representing 20 different cancers revealed that amplification of miR-181a correlated with poor outcome. Most recently, we have uncovered a novel mechanism through which miR-181a can drive tumor development at the earliest stage through the cooperative targeting of RB1 and Stimulator of Interferon Genes (STING). Enhanced miR-181a promoted the growth of highly aggressive and genomically instable cells through the direct inhibition of STING, a key activator of interferon signaling in response to cytoplasmic DNA. Though activating anti-tumor immunity is increasingly being recognized as an important therapy in cancer treatment the efficacy of current immunotherapies for the treatment of HGSC has not been successful mainly due to the highly immunosuppressive microenvironment. One of the primary means by which a tumor creates an immunosuppressive microenvironment is by inhibiting STING signaling within the tumor. Thus, our novel finding showing that miR-181a directly regulates STING introduced unique opportunity to assess whether therapeutic targeting of the miR-181a will reactivate IFN signaling via STING to overcome immune tolerance that is commonly seen in HGSC tumors.

“The Role of piRNA in Environmental Epigenetics”
Bambarendage Pinithi Perera, Ph.D.
Research Assistant Professor
Environmental Health Sciences
School of Public Health
Keywords: piRNA, epigenetics, toxicology
Abstract: Piwi-interacting RNAs (piRNAs) are small non-coding RNAs that associate with PIWI proteins to induce DNA methylation for retrotransposon suppression. Mature germline piRNAs typically consist of 24–32 nucleotides with a strong preference for a 5ʹ uridine, an adenine at position 10, and a 2ʹ-O-methylated 3ʹ end. In the current study, we identified piRNAs and associated machinery from mouse somatic tissues by quantifying Piwil1, Piwil2, and Piwil4 expression in brain, liver, kidney, and heart. The study revealed 26 piRNA sequence species and 40 piRNA locations exclusive to all examined somatic tissues. Non-coding RNA expression is sensitive to environmental exposures, although it has been unclear whether exposures such as lead (Pb) impact piRNA expression. In the current study, mouse dams were exposed to Pb 2 weeks prior to mating which continued through offspring weaning. We profiled tissue- and sex-specific effects of perinatal Pb exposure on the piRNA transcriptomes of the resulting progeny at 5 months. Based on significant p-values (<0.05), 346 piRNAs were differentially expressed among Pb-exposed mice in testes, 339 in ovaries, 127 in M cortex, 105 in F cortex, 42 in M liver, and 59 in F liver. According to preliminary results, a total of 3 piRNAs were
differentially expressed based on FDR(q<0.05). Although piRNA expression has long been considered exclusive to the germline, our results support previous reports of somatic piRNA expression, and demonstrate that perinatal environmental exposures such as Pb influence longitudinal piRNA expression in a tissue- and sex-specific manner.

RNA Innovation Seminar: Selene L. Fernandez-Valverde, Ph.D.
2022-06-06 16:00 - 17:00
“Long non-coding RNAs as evolutionarily fluid chromatin weavers”
Selene L. Fernandez-Valverde, Ph.D.
Principal Investigator
Advanced Genomics Unit
LANGEBIO, Cinvestav

Flyer in PDF
HYBRID SEMINAR:
In-person: BSRB, ABC seminar rooms
Zoom: https://umich.zoom.us/webinar/register/WN_3ga-wcUYSgqPEKw57DSfpg
Keywords: lncRNAs, Genomics, Genome topology
Abstract: Long non-coding RNAs (lncRNAs) have recently emerged as prominent elements of the regulatory transactions of eukaryotic genomes. Many of the know regulatory functions of lncRNAs in both animals and plants rely on the rearrangement of chromatin through direct interactions or recruitment of chromatin-modifying elements. In this talk, I will discuss the difficulty in identifying evolutionary conservation in lncRNAs, and how we characterize these evolutionarily volatile elements in the context of their role as regulators of the three-dimensional conformation of nuclear chromatin. I will focus on our findings resulting from the concurrent characterization of transcripts, tridimensional chromatin structure and direct RNA-DNA interactions in closely related plant species. I will also discuss how such techniques have vast potential to illuminate biomedically relevant lncRNAs when analyzed from a comparative genomics perspective.

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.

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: 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 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: 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 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 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: 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 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: 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: 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: 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.
