- Massachusetts Institute of Technology, Cambridge, MA, U.S., Research Fellow, 1992-1998.
- University of London, London, U.K. and EMBL, Heidelberg, Germany, PhD in Biochemistry, 1991.
- Imperial College of Science Technology and Medicine, University of London, U.K. BSc (hons) in Microbiology, 1988.
- Department of Molecular Genetics, University of Toronto.
MY RESEARCH OVERVIEW (GO TO SCIENTIFIC OVERVIEW)
Discovery and characterization of RNA regulatory networks with critical roles in development and disease
My research team studies the mechanisms by which genes are regulated and coordinated to provide critical functions in mammalian cells. Our work primarily focuses on a step in gene expression referred to as RNA splicing. This step is required for the expression of essentially all human genes. Moreover, alternative splicing decisions allow cells to greatly expand the repertoire of structurally and functionally distinct RNA transcripts and proteins from a limited number of genes. Recent work from our laboratory and others has shown that this diversification process establishes complex regulatory networks required for animal development. We are using a broad range of approaches, from focused biochemical studies to high-throughput sequencing, functional genomics, and bioinformatic analyses, to understand the function and regulation of networks of protein variants generated by alternative splicing. Our research is also directed at elucidating how altered splicing patterns cause and contribute to human disorders and diseases, including autism and cancers. This work has opened up exciting new therapeutic strategies, which we are currently also pursuing.
SCIENTIFIC RESEARCH OVERVIEW
Our current research is determining how alternative splicing (AS) networks are integrated with orthogonal gene regulatory layers – including chromatin/epigenetic modification, transcription, mRNA 3´end processing, turnover, and translation – to control fundamental normal and disease-associated biology. To this end, we have developed a powerful new technology to systematically identify trans-acting factors that control endogenous RNA regulatory events, as well as the first method enabling the unbiased, global-scale mapping of RNA-RNA interactions in vivo. These systems have identified dozens of new and unexpected protein- and RNA-based regulators, providing the basis for novel insight into mechanisms underlying the control and integration of gene regulatory layers. We will harness these and complementary strategies to characterize RNA regulatory networks associated with cell fate and human disease. For example, we will employ our technologies, and a new mouse model, to identify small molecules that rescue microexon mis-regulation and autism-associated phenotypes. Our highly integrative, multidisciplinary and collaborative research program will thus continue to elucidate fundamental mechanisms underlying gene regulation, and we will use this information to develop new therapeutic strategies.
Selected current projects:
1. Elucidation of cis- codes that control post-transcriptional gene regulation
Extending our pioneering work elucidating features of the splicing code (with Brendan Frey and colleagues, Barash et al. Nature, 2010), we are striving to decipher a more complete code that accounts for all classes of alternative splicing, including 3-27 nucleotide-long microexons, as well as other steps in post-transcriptional gene regulation such as mRNA 3’ end processing (collaboration with Quaid Morris). Understanding a more complete RNA code is a key step in determining how genes are regulated and how mutations and other forms of genetic variation cause or contribute to human disease.
2. Discovery of new trans-acting regulators that control cell fate
In collaboration with Jason Moffat and Jeffrey Wrana, we have developed a new functional genomics screen that allows the comprehensive identification of trans-acting factors that control endogenous RNA regulatory events of interest. This system is being applied to the discovery of new regulators of AS events that we have shown previously to play pivotal roles in the control embryonic stem cell pluripotency and neural differentiation (Gabut et al. Cell, 2011; Han et al. Nature, 2013). Information from this screen is thus providing a more complete picture of the regulatory networks that determine cell fate decisions. Moreover, we are harnessing this new information to devise methods for improving the efficiency and quality of production of induced pluripotent stem cells for research and therapeutic applications.
3. Microexons: regulation, function and roles in neurological disorders
We have recently used our transcriptome-wide profiling technology to discover a program of highly conserved and neuronal-specific, 3-27 nucleotide-long ‘microexons’ (Irimia et al. Cell, 2014). A remarkable feature of these tiny exons is that they are often misregulated in the brains of people with autism spectrum disorder. We have linked this altered regulation to the loss of expression of a neuronal-specific splicing regulator (nSR100/SRRM4) that was previously discovered in our lab (Calarco et al. Cell, 2009). Our current research is directed at using a new mouse model for nSR100 deficiency, developed in collaboration with Sabine Cordes (Quesnel-Vallieres et al. Genes Dev. 2015), to investigate the role of this regulator and its target microexon program in nervous system development and disorders. Importantly, these studies are beginning to shed light on a possible new therapeutic strategy for autism that may be applicable to a substantial fraction of individuals with this disorder.
4. Exploring the functions of non-coding RNAs through the systematic mapping of RNA-RNA interactions in vivo.
More than half of the human genome is transcribed into RNA. A major challenge in biological research is therefore to determine which of the myriad of transcripts that lack apparent protein-coding capacity provide important functional roles. Similarly, numerous abundant and conserved transcripts that bear hallmarks of previously characterized non-coding RNAs, such as small nucleolar RNAs, have been identified but also lack defined functions. To address these challenges, we have recently developed a new method that allows the systematic mapping of RNA-RNA interactions in vivo, referred to as ‘LIGR-Seq’. This method detects RNA-RNA duplexes cross-linked in vivo, through the ligation of proximal free ends, followed by sequencing of the resulting chimeric junctions. Using LIGR-Seq, we have detected thousands of novel RNA-RNA interactions that yield valuable testable hypotheses as to the possible functions of previously uncharacterized long and short non-coding RNAs. In future work we will investigate these new functions, and also apply LIGR-Seq to uncover regulatory landscapes controlled by RNA-RNA interactions during cell fate determination and in the context of human diseases.
- Global Mapping of Human RNA-RNA Interactions. Sharma E., Sterne-Weiler T., O'Hanlon D., Blencowe B.J. Mol Cell. 2016 May 11.
- An alternative splicing event amplifies evolutionary differences between vertebrates. Gueroussov, S., Gonatopoulos-Pourtnazis, T., Irimia, M., Raj, B., Lin, Z.Y., Gingras, A.C. and Blencowe, B.J. Science 2015 Aug 349(6250): 868-873.
- A highly conserved program of neuronal microexons is misregulated in autistic brains. Irimia, M., Weatheritt, R.J., Ellis, J., Parikshak, N.N., Babor, M., Quesnel-Vallieres, M., Tapial, J., Gonatopoulos-Pourtnazis, T., Raj, B., O’Hanlon, D., Barrios-Rodiles, M., Sternberg, M.J.E., Wrana, J.L., Roth, F.P., Geschwind, D.H., and Blencowe, B.J. Cell. 2014 Dec 18;159(7):1511-23.
View Pubmed search of Dr. Blencowe's full list of publications.