A major challenge in biology is to understand how the wealth of cellular and regulatory complexity emerges from a single genomic sequence. Decades of research have revealed that the fine-tuning of multiple, robust layers of gene regulation are essential to achieving this goal. However, important challenges remain in understanding the interconnections between these layers and how evolution acts to expand their complexity.

The Weatheritt Group focuses on the regulatory connectivity between the transcriptome and the proteome. In particular, we explore the inter-connections between alternative pre-mRNA splicing (AS - the process by which multiple, distinct transcript and protein variants are expressed from a single gene) and intrinsically disordered regions (IDRs - the sections of proteins which adopt an ensemble of conformations, rather than defined three-dimensional structures, and frequently embed short linear motifs). Our work has revealed strong connections between these layers, as alternatively spliced exons (including those subject to tissue- and lineage-specific control) show a strong tendency to regulate interactions involving IDRs. Importantly, we have also demonstrated that this regulation is able to feed back to control transcriptomic diversity.

To investigate these areas of interest, we undertake large computational screens using the wealth of publicly available data to generate experimentally testable hypotheses. This involves the use of existing approaches and the development of new methodologies. A recent example of this is the development of Whippet, a light-weight method for the rapid quantitative profiling of AS from raw RNA-Seq reads at the event-level.

We aim to continue investigating the role of lineage- and tissue-specific alternative splicing in expanding protein function.

Of particular interest will be integrating and developing approaches to exploit the recent data explosion associated with single-cell and long-read sequencing data, as well as with structural data of macromolecular complexes.

Moreover, recent unexpected observations of the importance of alternative splicing in cancer and autism spectrum disorder means we will continue to pursue these unexpected avenues
of research into understanding the molecular basis of complex disorders.

The Weatheritt group aims to understand how post-transcriptional regulation contributes to proteomic diversity and cell signalling.

Published In

Gueroussov S, Weatheritt RJ, O’Hanlon D, Lin ZY, Gingras AC, Blencowe BJ. (2017)

Mammalian-specific regulation of higher-order hnRNP protein assemblies controls alternative splicing.

Cell, 170(2): 324-339.

Weatheritt RJ, Sterne-Weiler T, Blencowe BJ. (2016)

The ribosome-engaged landscape of alternative splicing.

Nat Struct Mol Biol. 23(12): 1117-1123.

Irimia M, Weatheritt RJ, Ellis JD, Parikshak NN, Gonatopoulos-Pournatzis T, Babor M, Quesnel-Vallières M, Tapial J, Raj B, O'Hanlon D, Barrios-Rodiles M, Sternberg MJ, Cordes SP, Roth FP, Wrana JL, Geschwind DH, Blencowe BJ. (2014)

A highly conserved program of neuronal microexons is misregulatedin autistic brains.

Cell, 159(7):1511-23.

Weatheritt RJ, Babu MM. (2013)

Evolution: The hidden codes that shape protein evolution.

Science, 342(6164).