Our lab investigates the regulatory connectivity between protein layers to understand complex disorders.
Understanding how the wealth of cellular and regulatory complexity emerges from a single genomic sequence is a major challenge. Decades of research have revealed that the fine-tuning of multiple, robust layers of gene regulation are essential to achieve this goal. However, important challenges remain in understanding the interconnections between these layers and how complex disorders alter their integrity. Our group focuses on the regulatory connectivity between the transcriptome and the proteome. Of particular interest are the interconnections 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). Our work has revealed strong connections between these layers, as alternatively spliced exons – including those subject to tissue-and disease-specific changes – show a tendency to regulate interactions involving IDRs. Importantly, we have also demonstrated that this regulation can feed back to control transcriptomic diversity in disease.
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 using existing approaches and developing new methodologies. For example, our lab has developed Whippet – a light-weight method for the rapid quantitative profiling of AS from raw RNA-seq reads at the event-level.
Our ultimate objective is to identify new regulatory principles and features of regulatory systems. We aim to exploit these findings to better understand the regulatory dysfunctions leading to human diseases. An example of this is our observations of the importance of alternative splicing in cancer and autism spectrum disorder. We will continue to pursue these unexpected avenues of research, to further understand the molecular basis of complex disorders.