Jeremy E Wilusz, Ph.D.

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Assistant 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 work has focused on the MALAT1 locus, which is over-expressed in many human cancers and 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 in vivo. We recently showed that the 3’ end of MALAT1 is protected from 3’-5’ exonucleases by a highly conserved triple helical structure. Surprisingly, when this structure is placed downstream from an open reading frame, the transcript is efficiently translated in vivo despite the lack of a poly(A) tail. This result challenges the common paradigm that long poly(A) tails are required for efficient protein synthesis and suggests that non-polyadenylated RNAs may produce functional peptides in vivo via mechanisms that are likely independent of poly(A) binding protein. To address these issues, we are currently elucidating the molecular mechanism by which a triple helix functions as a translational enhancer. In addition, we are developing approaches to identify additional triple helices that form across the transcriptome, thereby revealing new paradigms for how RNA structures regulate gene expression.

Besides MALAT1, only a handful of long RNA polymerase II transcripts (e.g. histone mRNAs) have been clearly shown to be processed at their 3’ ends via non-canonical mechanisms. This is likely because nearly all previous studies characterizing the transcriptome have focused only on polyadenylated RNAs, thereby missing RNAs that lack a poly(A) tail. Nevertheless, it is becoming increasingly clear that non-polyadenylated RNAs are much more common and play significantly greater regulatory roles in vivo than previously appreciated. For example, an abundant class of circular RNAs has recently been identified in human and mouse cells. Two of these circular RNAs clearly function as microRNA sponges, but it is largely unknown why all the other circular RNAs are produced or how the splicing machinery selects certain regions of the genome (and not others) to circularize. We aim 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 noncoding RNAs with important biological functions.

Selected Publications

Wilusz Jeremy E, Sharp Phillip A: Molecular biology. A circuitous route to noncoding RNA. Science (New York, N.Y.) 340(6131): 440-1, Apr 2013.

Wilusz, Jeremy E.: Noncoding RNA. Brenners Online Encyclopedia of Genetics. 2nd Edition. Maloy, S. and Hughes, K. (eds.). 2013.

Wilusz Jeremy E, JnBaptiste Courtney K, Lu Laura Y, Kuhn Claus-D, Joshua-Tor Leemor, Sharp Phillip A: A triple helix stabilizes the 3' ends of long noncoding RNAs that lack poly(A) tails. Genes & Development 26(21): 2392-407, Nov 2012.

Wilusz Jeremy E, Whipple Joseph M, Phizicky Eric M, Sharp Phillip A: tRNAs marked with CCACCA are targeted for degradation. Science (New York, N.Y.) 334(6057): 817-21, Nov 2011.

Wilusz Jeremy E, Spector David L: An unexpected ending: noncanonical 3' end processing mechanisms. RNA (New York, N.Y.) 16(2): 259-66, Feb 2010.

Wilusz Jeremy E, Sunwoo Hongjae, Spector David L: Long noncoding RNAs: functional surprises from the RNA world. Genes & Development 23(13): 1494-504, Jul 2009.

Sunwoo Hongjae, Dinger Marcel E, Wilusz Jeremy E, Amaral Paulo P, Mattick John S, Spector David L: MEN epsilon/beta nuclear-retained non-coding RNAs are up-regulated upon muscle differentiation and are essential components of paraspeckles. Genome Research 19(3): 347-59, Mar 2009.

Wilusz Jeremy E, Freier Susan M, Spector David L: 3' end processing of a long nuclear-retained noncoding RNA yields a tRNA-like cytoplasmic RNA. Cell 135(5): 919-32, Nov 2008.

Wilusz Jeremy E, Beemon Karen L: The negative regulator of splicing element of Rous sarcoma virus promotes polyadenylation. Journal of Virology 80(19): 9634-40, Oct 2006.

Wilusz Jeremy E, Devanney Sean C, Caputi Massimo: Chimeric peptide nucleic acid compounds modulate splicing of the bcl-x gene in vitro and in vivo. Nucleic Acids Research 33(20): 6547-54, 2005.

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Last updated: 09/08/2014
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