Our highly collaborative research program utilizes a broad range of approaches to study fundamental questions relevant to RNA biology.

We have pioneered the development and application of technologies for the genome-wide quantitative profiling of transcriptomes1,2, RNA interactomes3, as well as new CRISPR-based and other functional genomics methods designed to elucidate RNA regulatory networks4-7. These efforts are uncovering remarkable landscapes of regulation that await further investigation.

Much of our research is focused on understanding the regulation, roles and evolution of alternative splicing regulatory networks, in particular those that are critical for nervous system development and function. For example, we have discovered and characterized a highly conserved program of switch-like alternative splicing events comprising 3-27 nucleotide-long neuronal "microexons" 8,9. We have shown that these tiny exons are important for the regulation of protein interactions with critical roles in nervous system development and cognitive functioning10, and have observed evidence that their disruption represents a convergent mechanism linked to autism spectrum disorder11. These findings raise exciting possibilities for the development of new therapeutic strategies. Current work is being directed at applying our new CRISPR-based approaches to systematically investigate the functions of microexons.

Expanding on our previous work elucidating fundamental features of the splicing code12-14, we are striving to decipher a more complete code that models both linear and structural RNA elements, and which accounts for all classes of alternative splicing, as well as other steps in RNA-regulation. This work encompasses investigations of the sequence code that governs the regulation of microexons and how this code is impacted by autism-linked genetic variation. Our current work on splicing mechanisms extends to understanding the evolution and function of higher-order protein complexes, including nuclear speckles and 40S hnRNP "ribonucleosome" particles15,16,17. Finally, we are studying the biological significance of biased composition regions of the proteome, including multifaceted roles of rare codon patches in gene regulation and disease.

Our research group comprises a team of highly talented experimental and computational scientists working at the University of Toronto Donnelly Centre, and in our recently established satellite laboratory, located in the Centre for Developmental Neurobiology at King's College London and the Francis Crick Institute. Together with the London group and collaborators, we are developing new therapeutic strategies aimed at selectively rescuing functional homeostasis to pathogenically-altered neurons in the context of brain disorders.

Our research is supported by grants from the Canadian Institute of Health Research, Wellcome Trust, Simons Foundation, Canada Foundation of Innovation, and the NOMIS Foundation.

Selected References

  1. Pan, Q. et al. Revealing global regulatory features of mammalian alternative splicing using a quantitative microarray platform. Mol Cell 16, 929-41 (2004).
  2. Pan, Q., Shai, O., Lee, L.J., Frey, B.J. & Blencowe, B.J. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nature Genetics 40, 1413-1415 (2008).
  3. Sharma, E., Sterne-Weiler, T., O'Hanlon, D. & Blencowe, B.J. Global Mapping of Human RNA-RNA Interactions. Mol Cell 62, 618-26 (2016).
  4. Han, H. et al. Systematic exploration of dynamic splicing networks reveals conserved multistage regulators of neurogenesis. Mol Cell 82, 2982-2999 e14 (2022).
  5. Han, H. et al. Multilayered Control of Alternative Splicing Regulatory Networks by Transcription Factors. Mol Cell 65, 539-553 e7 (2017).
  6. Gonatopoulos-Pournatzis, T. et al. Genetic interaction mapping and exon-resolution functional genomics with a hybrid Cas9-Cas12a platform. Nat Biotechnol 38, 638-648 (2020).
  7. Li, J.D., Taipale, M. & Blencowe, B.J. Efficient, specific, and combinatorial control of endogenous exon splicing with dCasRx-RBM25. Mol Cell (2024).
  8. Irimia, M. et al. A highly conserved program of neuronal microexons is misregulated in autistic brains. Cell 159, 1511-23 (2014).
  9. Gonatopoulos-Pournatzis, T. et al. Genome-wide CRISPR-Cas9 Interrogation of Splicing Networks Reveals a Mechanism for Recognition of Autism-Misregulated Neuronal Microexons. Mol Cell 72, 510-524 e12 (2018).
  10. Gonatopoulos-Pournatzis, T. et al. Autism-Misregulated eIF4G Microexons Control Synaptic Translation and Higher Order Cognitive Functions. Mol Cell 77, 1176-1192 e16 (2020).
  11. Quesnel-Vallieres, M. et al. Misregulation of an Activity-Dependent Splicing Network as a Common Mechanism Underlying Autism Spectrum Disorders. Mol Cell 64, 1023-1034 (2016).
  12. Barash, Y. et al. Deciphering the splicing code. Nature 465, 53-59 (2010).
  13. Barbosa-Morais, N.L. et al. The evolutionary landscape of alternative splicing in vertebrate species. Science 338, 1587-93 (2012).
  14. Braunschweig, U. et al. Widespread intron retention in mammals functionally tunes transcriptomes. Genome Res 24, 1774-86 (2014).
  15. Gueroussov, S. et al. An alternative splicing event amplifies evolutionary differences between vertebrates. Science 349, 868-73 (2015).
  16. Gueroussov, S. et al. Regulatory Expansion in Mammals of Multivalent hnRNP Assemblies that Globally Control Alternative Splicing. Cell 170, 324-339 e23 (2017).
  17. Barutcu, A.R. et al. Systematic mapping of nuclear domain-associated transcripts reveals speckles and lamina as hubs of functionally distinct retained introns. Mol Cell 82(5), 1035-1052.e9 (2022).

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