FALL 2018 RNA BIOSCIENCE INITIATIVE

About the RNA Bioscience

Initiative Modern biology has been revolutionized by the discovery that many processes of fundamental importance are regulated by RNA. Major knowledge gaps remain in the basic, diagnostic and therapeutic areas of RNA biology and much remains to be discovered about mechanisms of RNA regulation and their impact on

biology and disease. The mission of the  RNA Bioscience Initiative (RBI) is to create and expand a vibrant center of discovery and innovation in RNA research (RNAbio.co)(follow us on Twitter @rnabioco).

The RNA Bioscience Initiative was started in the Summer of 2016 with $20 million in funding from the Dean’s Office of the University of Colorado School of Medicine. The importance of RNA biology was recently described by the National Cancer Institute in this way: “RNA biology has emerged as one of the most influential areas in modern biology and bioscience. The discovery of

numerous new classes of RNAs and their function in a wide spectrum of biological processes has revolutionized molecular biology and has profound implications for clinical sciences. Key areas of current research include the elucidation of RNA biogenesis and structure, the identification of functions for various classes of RNAs, establishing the role of RNA in disease, and the exploration of RNA-based- and RNA-targeted therapies.” Researchers have only scratched the tip of the iceberg in

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About RNA and

the RNA Bioscience Initiative

Promoting Basic and Applied RNA

Research NEW RBI FACULTY

GRANTS PROGRAMS Bioinformatics

Single Cell RNA-seq RNA-seq

RNA Biology DOM Outstanding

Scholars

EDUCATION RNA Scholars

Summer Interns Seminars

Evening with RNA

Promoting Basic and Applied RNA

Research

RBI NEWSLETTER

FALL 2018 RNA BIOSCIENCE INITIATIVE

realizing the potential of RNA regulatory mechanisms to illuminate biology and advance medicine through development of new therapeutics.  RNA therapeutics have the potential to revolutionize development of new treatments as strategies can be implemented to target virtually any disease or process through a common target, RNA. Investigators on campus have already made important discoveries in the field, covering RNA structure-function, RNA biogenesis, non-coding regulatory RNAs in disease, RNA methods development, and mechanisms of gene regulation by non-coding RNAs. In the past two years, RBI Faculty continue to increase our understanding of RNA biology and disease with recent publications in Science, Nature Communications, Molecular Cell, Genes and Development, RNA, and Genome Research.

The mission of the RNA Bioscience Initiative is to understand the role of RNA in biology, engage in collaborative research, apply approaches from basic science to translational efforts, and train the next generation of researchers. The RBI aims to facilitate basic and applied RNA research through new faculty hires and a spectrum of grant, bioinformatic, educational, and community programs. The RNA Bioscience Initiative aims to promote and support RNA research to answer a number of questions including: • What are the RNAs that drive biological outcomes in healthy

and diseased cells, how does their expression change, and how is this regulated?

• What are the downstream biological effects that are driven by diverse RNAs and how are these RNA-based processes regulated?

• How do these RNAs elicit their effects and what are the details of their mechanisms of action?

• Can we exploit this knowledge to create better RNA-based research tools, diagnostics, and therapies that either use RNA or target it?

About RNA The genetic material, DNA, encodes all the requisite information to produce all cells, tissues, and a complete organism. Genes embedded in the DNA are copied into a message, called messenger RNA (mRNA), that is then decoded or translated into proteins using a code of a combination 3 letters words (composed of A, C, G, U) that define the composition of a protein. Proteins in large part are what make up cells. Our bodies have many different cells. Different proteins made and used in each of these cells define the unique characteristics of each cell type. DNA in each

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RNA Day with Summer Interns

Single Cell RNA-seq

RNA Day with Summer Interns

An Evening with RNA

Informatic Fellows and Jay Hesselberth

FALL 2018 RNA BIOSCIENCE INITIATIVE

cell contains all genes, but only a subset of genes are used in each cell to produce the unique set of proteins that determine what type of cell is made. Each gene produces a protein encoding mRNA that undergoes a series of important steps in their maturation, including processing of the RNA (such as splicing), before they are decoded or translated into a protein. The processing of an RNA is highly regulated. However, if errors are made in this maturation and processing, this can often lead to disease. Similarly, mutations in DNA that lead to changes in the RNA can

i m p a c t R N A p r o c e s s i n g /maturation and the proteins they encode. Understanding how R N A s a r e m a d e , processed, matured, and translated is key to understanding how errors can lead to disease. Greater t h a n 3 0 % o f a l l genetic diseases are a consequence of RNA p r o c e s s i n g /

maturation. In addition, many viruses of broad health and economic impacts are based primarily on RNA, even encoding their genetic information in RNA. Not all genes in DNA encode mRNAs that produce proteins. Many genes encode RNAs that do not encode proteins and are thus called non-coding RNAs. There are many different types of non-coding RNAs, all of which play key roles in cells. Over the past few years, the number, function, and key importance of these non-coding RNAs has been recognized. These non-coding RNAs control or regulate other genes through a variety of mechanisms.

RNA Therapy The discovery and characterization of these different types of RNA and their cellular functions has led to a revolution in RNA biology. Understanding the function and action of these RNAs has enabled the development of new RNA-based tools that mimic or antagonize the function of these novel RNAs for RNA-based strategies to generate new types of therapeutics in a variety of diseases. RNA therapeutics have the potential to revolutionize development of new treatments as strategies can be implemented to target RNAs associated with virtually any disease or process through RNA interference. RNA analogs are being used and developed take advantage of complementary base-pairing to mimic or antagonize cellular RNA processes.

The painstaking development of drugs to target a specific protein requires in depth study, many years, high cost, and often luck. New RNA technologies enable simply targeting the RNA that encodes the protein using relatively simple and common principles of base-pairing. New RNA-related therapies are now available or in the pipeline to provide proteins to enable blot clotting in hemophilia, to target and remove RNAs that contribute to a variety of diseases (optic

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FALL 2018 RNA BIOSCIENCE INITIATIVE

neuropathy, familial TTR amyloidosis, hepatitis C, hypercholesterolemia, hemophilia, porphyria, etc.), to ameliorate RNA maturation/processing defects such as in spinal muscular atrophy (SMA)(Spinraza) and Duchenne’s muscular dystrophy (Exondys 51), and personalized RNA vaccines for cancer therapy. RNA vaccines for cancer therapy. RNAs as biomarkers also have enormous untapped potential for disease diagnostics.

The goal of the RNA Bioscience Initiative is to support basic and applied research in RNA biology to generate new and novel insights into the role of RNA in health and disease and provide new tools and targets for RNA research, diagnostics and therapies.

New RBI Faculty The RNA Bioscience Initiative was fortunate to attract a number of new outstanding faculty to the

Anschutz Medical Campus. The new faculty are (left to right in picture) Sujatha Jagannathan (mRNA surveillance in health and disease), Olivia Rissland (RNA stability and translation), Neelanjan Mukherjee (Systems biology of human RNA regulatory networks), Matthew Taliaferro (Subcellular RNA localization), and Srinivas Ramachandran (In vivo nucleosome structure and dynamics). The RBI thanks the UC Cancer Center for contributing startup funds for Drs. Mukherjee and Ramachandran. The new faculty are off to a running start with new graduate students, PRAs, and postdocs in their labs as well as new funding. Dr. Rissland was awarded a 5 year R35 grant for

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FALL 2018 RNA BIOSCIENCE INITIATIVE

Early Stage Investigators through the NIH Institute of General Medical Sciences, Dr. Taliaferro was awarded a Webb-Waring Biomedical Research Grant from the Boettcher Foundation, and Dr. Jagannathan awarded a Research Grant through the Friends of FSH Research. Drs. Taliaferro and Jagannathan were nominated for the Pew Scholars in the Biomedical Sciences and Searle Scholars Programs, respectively. These programs support young investigators of outstanding promise in science relevant to the advancement of human health.

Significant effort has also been made in trying to recruit several candidates (senior and junior) as new faculty in the area of RNA therapy to enhance the translational/clinical efforts of RBI. However, these recruitments are challenging and have not been successful.

RBI Grants Programs The RBI has initiated a variety of Grant Programs and support for new technologies (e.g., single cell RNA sequencing). $1.5 million have been allocated to these programs to date and the most recent awards were made this August. The current RBI Grant Programs include RNA Bioinformatics Support, Single-Cell RNA-seq Instrumentation and Awards, RNA-seq Awards, RNA Biology Awards, and support for the Department of Medicine Outstanding Early Career Scholars. For information on future awards, request to be added to the RBI-listserve by contacting RNA.Bioscience@ucdenver.edu. We encourage applications from experienced investigators and newcomers to RNA Biology.

The RBI informatics post-doctoral fellows led by Dr. Jay Hesselberth provide RNA informatics support for the RBI grants program. The RBI fellows include Kent Riemondy, Austin Gillen, and Rui Fu, all of which have significant biomedical expertise and experience in experimental RNA biology. The RBI Fellows have initiated 87 projects with 60 different investigators (see https://rnabioco.github.io/rbi-project-summary/ ). These include 72 projects initiated from grant and pilot programs funded by the RBI. Forty four single-cell RNA sequencing experiments have been initiated with investigators across campus. The fellows also work on independent projects. These projects have led to publications in Nature Medicine, Nucleic Acids Research, and RNA.

Several symposia with research presentations by awardees from the grant programs have been held on campus. These programs have supported and led to the submission of at least 14 grants with a number awarded from the NSF and DOD and others still pending review. Publications supported by the grants programs include papers in Nature Communications, PLOS Pathogens, RNA, Experimental Hematology, RNA Biology, Molecular Carcinogenesis, and AIDS with a number of papers currently in review.

In an effort to support research and scientists in clinical departments, the RBI has recently partnered with the Department of Medicine Outstanding Early Career Scholars Program to provide financial support for one of its scholars, Dr. Beth Tamburini.

The RBI has also contributed to the Structural Biology effort on campus through faculty hiring, equipment, and other support.

While it is early to evaluate the overall impact of these programs, we see that these programs are making an impact on campus.

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FALL 2018 RNA BIOSCIENCE INITIATIVE

Upcoming RBI RFA to Support Collaborative Research Between Clinical/Translational and Basic Scientists A goal of the RBI is to interface with and support clinical and translational RNA research. The RBI will be announcing a program in the near future to support collaborative research between clinical/translational and basic scientists in an effort to develop long-term research collaborations that will exploit applied and basic science expertise toward important health related problems.

Increasing Need for Bioinformatic Education, Support, and Capacity The RBI through the RBI Informatic Fellows program aims to provide support for RNA bioinformatics. The RBI Informatic Fellows are post-doctoral positions that encourage independent research while providing support for RNA informatics. The RBI Informatics Fellows are not a core or service provider and thus their services are limited. The RBI recognizes that the Fellows Program only scratches the surface of the RNA informatics need on campus.

Jay Hesselberth, who guides the fellows, has provided courses for basic scripting and bioinformatic tools including the Genome Analysis Workshop (MolB 7621) and in the Graduate Core Course (Exploratory Biological Data Analysis with R and RStudio, IDPT 7810). This Spring the new RBI Faculty (Drs. Jagannathan, Mukherjee, Ramachandran, and Taliaferro) will offer several new courses in basic informatics including Practical computational biology for biologists: Python (MolB 7900 ) and Practical computational biology for biologists: R (MolB 7950) in an effort to provide basic instruction and a foundation for informatic analyses. The RBI recognizes that the use of informatics is a core component of biomedical research and needs to be strongly incorporated into the curriculum to provide the foundation for its use in research.

Bioinformatics has become an integral part of biomedical science, crosses many disciplines, and is used to enable a variety of research. The RBI hopes though educational courses and limited services to increase and improve bioinformatic capability on campus. However, the breadth of different types of bioinformatic analysis (including DNA analysis and many others), training required, and long-term support and availability for the biomedical research enterprise on campus is a critical need that needs to be addressed for our campus to maintain research competitiveness.

RBI Educational Programs An important component of the RBI are the Educational Programs. These programs include support for graduate students (the RNA Scholars), RBI informatics post-doctoral fellows, undergraduate summer intern research program, travel awards for students and post-doctoral fellows, RNA seminars, and a joint RNA Club with RNA researchers at UC Boulder called “An Evening with RNA”.

The summer intern research program provides support for undergraduates to carry out summer research. Thirty students in 20 different labs across the Anschutz campus have participated. The 10-week program organized by Dr. Aaron Johnson includes weekly RNA-related small group lunch seminars from core RBI faculty and mentoring lunches with PhD students and post-doctoral fellows.

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FALL 2018 RNA BIOSCIENCE INITIATIVE

The RNA scholars p r o g r a m p r o v i d e s support for graduates s t u d e n t s ( s t i p e n d , t u i t i o n , a n d supplemental funds) c a r r y i n g o u t R N A research. The program is supporting 5 students t h i s y e a r a n d h a s supported 12 students overall. These student are from a variety of g r a d u a t e p r o g r a m s i n c l u d i n g Pharmacology; Cell , S t e m C e l l , a n d Developmental Biology; I m m u n o l o g y a n d M i c r o b i o l o g y ; B i o c h e m i s t r y a n d Structural Biology; and Molecular Biology. The R N A s c h o l a r s h a v e published papers in G e n e s a n d Development, Molecular C e l l , N a t u r e C o m m u n i c a t i o n s , Structure, RNA, Journal of Proteome Research, and the Journal of Virology with a number of papers currently in review.

In an effort to promote RNA research, collaboration, and interaction, the RBI supports “An Evening with RNA” which is a joint venture between the RNA Clubs of UC Boulder and UC Anschutz. This program extends a long and important tradition started over 25 years ago in Boulder. These are held 8 times a year that alternate between the campuses. They include four presentations (two from each campus), food, and RBI provides bus transportation to the other campus to facilitate participation. This joint campus RNA venture is also supported by an award obtained by Jay Hesselberth and Suja Jagannathan from the RNA Society (https://www.rnasociety.org) known as an RNA Salon. RNA Salon awards support regional RNA science-based gatherings that cultivate year-long interaction, engagement, sharing of knowledge among RNA researchers and support of junior scientists.  Speakers for a recent “An Evening with RNA” held in Boulder included Dr. Jeffrey Kieft,

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FALL 2018 RNA BIOSCIENCE INITIATIVE

Dr. James Hagman, Mr. Gabriel Tauber, and Dr. Roy Parker. The events are announced through the RNA Bioscience List-serve (to be added to the list contact RNA.Bioscience@ucdenver.edu).

Finally, through this year, the RBI will have funded 40 seminar speakers in the CSD, Immunology and Microbiology, Pharmacology, Biochemistry, and Molecular Biology Seminar Programs. If you have an RNA speaker that you would like supported by the RBI, please contact RNA.Bioscience@ucdenver.edu.

RNA Bioscience Initiative Directors • David Bentley • Richard Davis

Bioinformatics Program • Jay Hesselberth

Summer Research Intern Program • Aaron Johnson

IT Support • David Farrell

Steering Committee • David Bentley • Richard Davis • Linda van Dyk • Jay Hesselberth • Aaron Johnson • Craig Jordan • Jeffrey Kieft • Eric Poeschla • Olivia Rissland

Administrator • Brittany Polson (rna.bioscience@ucdenver.edu)

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