Ph.D. 2012, Harvard-MIT Division of Health Sciences and Technology
"We seek to understand how regulation of RNA plays a role in maintenance of health and development of disease. Using a combination of high-throughput, genome-wide approaches and high-resolution, single-molecule approaches, we study gene expression, RNA splicing, RNA-protein interactions, and the subcellular localization of RNAs in order to link events at the molecular level to physiological changes that occur in myotonic dystrophy (the most common form of muscular dystrophy), cancer, and other contexts. From our studies of myotonic dystrophy, we have learned about not only general principles, but also specific RNAs and proteins that play key roles in development, cell differentiation, and cancer. We are actively involved in the development of therapies for these diseases, and collaborate extensively with others inside and outside the academic realm to reach these goals."
Eric Wang received his B.A. from Harvard College (2004), where he studied biochemistry. He received his Ph.D. in medical engineering/medical physics, with a focus on bioinformatics and integrative genomics, from the Harvard-MIT Division of Health Sciences and Technology (2012). During his doctoral thesis work, performed in the labs of Christopher Burge and David Housman, he established new tools for studying transcriptomes and RNA-protein interactions, and applied them to better understanding molecular events in neuromuscular disease. In 2012, Eric received a postdoctoral fellowship award from the Myotonic Dystrophy Foundation. In 2013, Eric received an NIH Director’s Early Independence Award, a NIH Common Fund grant aimed at accelerating the independent careers of exceptionally promising young scientists.
1) Understanding molecular pathogenesis in myotonic dystrophy and other RNA-mediated diseases
Myotonic dystrophy (dystrophia myotonica, DM) is the most common form of muscular dystrophy; however, it is a truly multi-systemic disease, affecting many parts of the body including skeletal muscle, the heart, the GI tract, the endocrine system, and the central nervous system. DM patients also experience an elevated risk for certain malignancies, such as hereditary non-polyposis colorectal cancer. DM is caused by an expanded microsatellite repeat, which is transcribed into mRNA; this mRNA exerts a toxic dominant effect via sequestration of particular RNA binding proteins. As a result, the splicing and/or localization of numerous mRNAs is perturbed. A key goal of the Wang laboratory is to connect molecular events to disease symptoms, and to derive general principles for how alterations to RNA binding protein metabolism drive disease progression. These principles will lead to significant insights in other RNA-mediated diseases, as well as cancer.
2) Defining cellular functions of localized RNAs, and identifying RNA and protein elements which mediate their localization
Some of the proteins involved in DM also regulate RNA localization, a next “frontier” in molecular and cell biology. While the localization of a small number of RNAs has been shown to be critical for their function, we currently hold a limited understanding of all the cellular components that play a role in this process. Using a combination of high-throughput, global approaches and high-resolution, single molecule approaches, the Wang laboratory aims to systematically identify these components. As a long-term goal, they seek to observe single RNA molecules in their native context, link their spatial regulation to function, and assess the contribution of mis-localized RNAs to disease.
3) Developing therapies for myotonic dystrophy, other RNA-mediated diseases, and cancer
Numerous strategies exist for DM therapeutics, including eliminating the expanded repeat tract, inhibiting transcription of the expanded repeat RNA, destroying the pathogenic RNA, and inhibiting pathogenic RNA-protein interactions. The Wang laboratory is pursuing some of these approaches in collaboration with others, and expects that their work in this area will translate readily to other RNA-mediated diseases, as well as cancer.
Hong Han, Manuel Irimia, P Joel Ross, Hoon-Ki Sung, Babak Alipanahi, Laurent David, Azadeh Golipour, Mathieu Gabut, Iacovos P Michael, Emil N Nachman, Eric Wang, Dan Trcka, Tadeo Thompson, Dave O'Hanlon, Valentina Slobodeniuc, Nuno L Barbosa-Morais, Christopher B Burge, Jason Moffat, Brendan J Frey, Andras Nagy, James Ellis, Jeffrey L Wrana and Benjamin J Blencowe. MBNL proteins repress ES-cell-specific alternative splicing and reprogramming. Nature, 498 (7453): 241-5, 2013.
Mohammadsharif Tabebordbar, Eric T Wang and Amy J Wagers. Skeletal muscle degenerative diseases and strategies for therapeutic muscle repair. Annu Rev Pathol, 8: 441-75, 2013.
Raman Parkesh, Jessica L Childs-Disney, Masayuki Nakamori, Amit Kumar, Eric Wang, Thomas Wang, Jason Hoskins, Tuan Tran, David Housman, Charles A Thornton and Matthew D Disney. Design of a bioactive small molecule that targets the myotonic dystrophy type 1 RNA via an RNA motif-ligand database and chemical similarity searching. J Am Chem Soc, 134 (10): 4731-42, 2012.
Jamie Purcell, Julia C Oddo, Eric T Wang and J Andrew Berglund. Combinatorial Mutagenesis of MBNL1 Zinc Fingers Elucidates Distinct Classes of Regulatory Events. Mol Cell Biol, 32 (20): 4155-67, 2012.
Maja M Janas, Eric Wang, Tara Love, Abigail S Harris, Kristen Stevenson, Karlheinz Semmelmann, Jonathan M Shaffer, Po-Hao Chen, John G Doench, Subrahmanyam V B K Yerramilli, Donna S Neuberg, Dimitrios Iliopoulos, David E Housman, Christopher B Burge and Carl D Novina. Reduced expression of ribosomal proteins relieves microRNA-mediated repression. Mol Cell, 46 (2): 171-86, 2012.
Eric T Wang, Neal A L Cody, Sonali Jog, Michela Biancolella, Thomas T Wang, Daniel J Treacy, Shujun Luo, Gary P Schroth, David E Housman, Sita Reddy, Eric L'ecuyer and Christopher B Burge. Transcriptome-wide Regulation of Pre-mRNA Splicing and mRNA Localization by Muscleblind Proteins. Cell, 150 (4): 710-24, 2012.
Christopher S Bland, Eric T Wang, Anthony Vu, Marjorie P David, John C Castle, Jason M Johnson, Christopher B Burge and Thomas A Cooper. Global regulation of alternative splicing during myogenic differentiation. Nucleic Acids Res, 38 (21): 7651-64, 2010.
Yarden Katz, Eric T Wang, Edoardo M Airoldi and Christopher B Burge. Analysis and design of RNA sequencing experiments for identifying isoform regulation. Nat Methods, 7 (12): 1009-15, 2010.
Daniel Ramsk"old, Eric T Wang, Christopher B Burge and Rickard Sandberg. An abundance of ubiquitously expressed genes revealed by tissue transcriptome sequence data. PLoS Comput Biol, 5 (12): e1000598, 2009.
Eric T Wang, Rickard Sandberg, Shujun Luo, Irina Khrebtukova, Lu Zhang, Christine Mayr, Stephen F Kingsmore, Gary P Schroth and Christopher B Burge.Alternative isoform regulation in human tissue transcriptomes. Nature, 456 (7221): 470-6, 2008.