Understanding alternative splicing in health and disease.
Using long-read DNA sequencing we can reveal the many, long-undiscovered forms that a single gene can take - leading us to new therapeutic targets.
Led by: Wilfried Haerty
UKRI Medical Research Council (MRC)
MDC Psychiatric Consortium
UKRI Biotechnology and Biological Sciences Research Council (BBSRC)
Around 95% of human genes undergo alternative splicing, the process by which multiple transcripts with different sequences are produced from a single gene.
Alternative splicing is a highly regulated process, and its disruption is associated with many disorders and diseases. Many primary candidate genes are broadly expressed which may have an impact on drug efficacy and toxicity.
Understanding how AS and its associated mechanisms - such as differential isoform expression or exon usage - work to parse genomic blueprints into the staggering diversity of known biological structures is one of the key themes underpinning our research.
We currently investigate how AS and associated regulatory processes shape the complex neurological and neuronal structures of the human brain, along with the impacts of misregulation or aberrant processes in the development of neuronal disorders. We are applying novel molecular and computational developments to help us understand AS diversity and regulation in cells, tissues, and across individuals. In particular, we utilise long-read sequencing technology, leveraging its ability to sequence long molecules to study whole transcripts, breakpoints, and splice junctions down to nucleotide resolution. This allows us to deliver comprehensive annotations of genes of interest and quantify transcript expression and usage across conditions. We work with a number of collaborators utilising both human brain tissue and in vitro cell line model systems.
In addition to annotating alternatively spliced transcripts and quantifying their expression, we are also investigating their regulation through the development of computational approaches to reconstruct regulatory networks, including splicing information. This allows us to better understand how regulatory elements in turn impact AS processes. We know that AS processes play a critical role in many diseases and so uncovering how AS is regulated or misregulated in these cases will help us to better understand the diseases themselves.
Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain
Long read sequencing reveals novel isoforms and insights into splicing regulation during cell state changes
Combined single-cell gene and isoform expression analysis in haematopoietic stem and progenitor cells
Alternative splicing (AS) is the process of generating multiple transcripts from a single gene through differential exon usage.
Nearly 95% of our genes undergo alternative splicing. AS is a highly-regulated process with significant evidence of a developmental stage, tissue, or cell-specific regulation. Dysregulation of the splicing machinery or of transcript splicing is directly associated with many disorders and diseases.
In close collaboration with industrial partners and collaborators at the University of Oxford, we are developing experimental and computational approaches to characterise splicing diversity, investigating splicing regulation, and identifying transcripts arising from candidate genes expressed specifically in a tissue of interest. Those transcripts will be primary candidates for further target development.