Faculty

Jeremy E Wilusz, Ph.D.

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Associate Professor of Biochemistry and Biophysics
Department: Biochemistry and Biophysics

Contact information
Department of Biochemistry & Biophysics
University of Pennsylvania Perelman School of Medicine
363 Clinical Research Building
415 Curie Boulevard
Philadelphia, PA 19104-6059
Office: 215-898-8862
Lab: 215-898-8863
Education:
B.S. (Molecular and Cellular Biology)
Johns Hopkins University, 2005.
Ph.D. (Biological Sciences)
Watson School of Biological Sciences, Cold Spring Harbor Laboratory, 2009.
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Description of Research Expertise

The sequencing of the human genome provided quite a surprise to many when it was determined that there are only ~20,000 protein-coding genes, representing less than 2% of the total genomic sequence. Since other less complex eukaryotes like the nematode C. elegans have a very similar number of genes, it quickly became clear that the developmental and physiological complexity of humans probably can not be solely explained by proteins. We now know that most of the human genome is transcribed, yielding a complex repertoire of RNAs that includes tens of thousands of individual noncoding RNAs with little or no protein-coding capacity. Among these are well-studied small RNAs, such as microRNAs, as well as many other classes of small and long transcripts whose functions and mechanisms of biogenesis are less clear – but likely no less important. This is because many of these poorly characterized RNAs exhibit cell type-specific expression or are associated with human diseases, including cancer and neurological disorders. Our goal is to characterize the mechanisms by which noncoding RNAs are generated, regulated, and function, thereby revealing novel fundamental insights into RNA biology and developing new methods to treat diseases.

Much of our recent work has focused on circular RNAs, which are generated from thousands of protein-coding genes. At some genes, the abundance of the circular RNA exceeds that of the associated linear mRNA by a factor of 10, raising the interesting possibility that the function of some protein-coding genes may be to produce circular noncoding RNAs, not proteins. These circular RNAs are generated when the pre-mRNA splicing machinery “backsplices” and joins a splice donor to an upstream splice acceptor. We showed that repetitive elements, e.g. SINE elements, in the flanking introns are critical determinants of whether the intervening exon(s) circularize. When repeat sequences from the flanking introns base pair to one another, the splice sites are brought into close proximity and backsplicing occurs. This knowledge allowed us to generate plasmids that efficiently produce any circular RNA in species ranging from humans to flies. Using high-throughput screening, we have further shown that the ratio of linear to circular RNA produced from a given gene is modulated by a number of factors, including hnRNPs, SR proteins, core spliceosome, and transcription termination proteins. Surprisingly, when spliceosome components were depleted or inhibited pharmacologically, the steady-state levels of circular RNAs increased while expression of their associated linear mRNAs concomitantly decreased. Inhibition or slowing of canonical pre-mRNA processing events thus shifts the steady-state output of protein-coding genes towards circular RNAs, which likely helps explain why and how circular RNAs show tissue-specific expression profiles. Once generated, we showed that most circular RNAs are exported to the cytoplasm using a length-dependent and evolutionarily conserved pathway. It still remains largely unclear what most circular RNAs do, although two are known to efficiently modulate the activity of microRNAs. Ongoing efforts aim to further elucidate the mechanisms by which circular RNAs are produced, regulated, and function to control cell physiology and impact human diseases.

Besides focusing on circular RNAs that have no 5’ or 3’ end, my lab has also provided important insights into how the 3’ ends of linear RNAs are generated and regulated. We showed that the MALAT1 locus, which is over-expressed in many human cancers, produces a long nuclear-retained noncoding RNA as well as a tRNA-like cytoplasmic small RNA (known as mascRNA). Despite being an RNA polymerase II transcript, the 3’ end of MALAT1 is produced not by canonical cleavage/polyadenylation but instead by recognition and cleavage of the tRNA-like structure by RNase P. Mature MALAT1 thus lacks a poly(A) tail, yet is expressed at a level higher than many protein-coding genes due to a highly conserved triple helical structure protecting its 3’ end. We continue to identify and characterize additional RNAs whose 3’ ends are generated via unexpected mechanisms, thereby revealing novel paradigms for how RNAs are processed and, most importantly, new classes of RNAs with important biological functions.

Selected Publications

Dodbele S, Mutlu N, Wilusz JE: Best practices to ensure robust investigation of circular RNAs: pitfalls and tips. EMBO Rep 22: e52072, Mar 2021.

Meganck RM, Liu J, Hale AE, Simon KE, Fanous MM, Vincent HA, Wilusz JE, Moorman NJ, Marzluff WF, Asokan A. : Engineering highly efficient backsplicing and translation of synthetic circRNAs. Mol Ther Nucleic Acids 23: 821-834, Jan 2021.

He C, Bozler J, Janssen KA, Wilusz JE, Garcia BA, Schorn AJ, Bonasio R: TET2 chemically modifies tRNAs and regulates tRNA fragment levels. Nat Struct Mol Biol 28: 62-70, Jan 2021.

Tatomer DC, Liang D, Wilusz JE: RNAi screening to identify factors that control circular RNA localization. Methods Mol Biol 2209: 321-332, 2021.

Mendoza-Figueroa MS, Tatomer DC, and Wilusz JE : The Integrator complex in transcription and development. Trends Biochem Sci 45: 923-934, Nov 2020.

Xiao MS, Ai Y, Wilusz JE: Biogenesis and functions of circular RNAs come into focus. Trends Cell Biol 30: 226-240, Mar 2020.

Elrod ND, Henriques T, Huang KL, Tatomer DC, Wilusz JE, Wagner EJ, Adelman K: The Integrator complex attenuates promoter-proximal transcription at protein-coding genes. Mol Cell 76: 738-752, Dec 2019.

Tatomer DC, Elrod ND, Liang D, Xiao MS, Jiang JZ, Jonathan M, Huang KL, Wagner EJ, Cherry S, Wilusz JE: The Integrator complex cleaves nascent mRNAs to attenuate transcription. Genes Dev 33: 1525-1538, Nov 2019.

Fujiwara R, Damodaren N, Wilusz JE, Murakami K: The capping enzyme facilitates promoter escape and assembly of a follow-on pre-initiation complex for re-initiation. Proc Natl Acad Sci USA 116: 22573-22582, Nov 2019.

Kearse MG, Goldman DH, Choi J, Nwaezeapu C, Liang D, Green KM, Goldstrohm AC, Todd PK, Green R, Wilusz JE: Ribosome queuing enables non-AUG translation to be resistant to multiple protein synthesis inhibitors. Genes Dev 33: 871-885, July 2019.

Xiao MS, Wilusz JE: An improved method for circular RNA purification using RNase R that efficiently removes linear RNAs containing G-quadruplexes or structured 3’ ends. Nucleic Acids Res 47: 8755-8769, July 2019.

Garikipati VNS, Verma SK, Cheng Z, Liang D, Truongcao MM, Cimini M, Yue Y, Huang G, Wang C, Benedict C, Mallaredy V, Ibetti J, Grisanti L, Schumacher SM, Gao E, Rajan S, Wilusz JE, Goukassian D, Houser S, Koch WJ, Kishore R: Circular RNA circFndc3b modulates cardiac repair after myocardial infarction via FUS/VEGF-A axis. Nat Commun 10: 4317, Sept 2019.

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Last updated: 08/02/2021
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