There is more than meets the eye: reconstruction of isoform level regulatory networks in the human brain

HAERTY_E22DTP

Therapies for many potentially treatable genetic diseases remain out of touch because we still don’t have a full picture of how genes are regulated differently between cells and tissues. Many genes, including some directly associated with traits and disorders, are widely expressed across cells and tissues, leading to potential unwanted secondary effects if blindly targeted with medications.

However, nearly all genes in humans undergo alternative splicing, the process through which different transcripts are generated from a single gene.

Recent work by us and others demonstrated that alternatively spliced transcripts arising from many of these genes tend to have a much more specific expression, opening the opportunity to identify specific isoforms as potential targets for drug development. To further the identification of isoforms of interest it is becoming increasingly important to fully characterise their regulation through the reconstruction of regulatory networks integrating splicing information in relevant tissues.

We offer a highly collaborative PhD project between the Haerty (bioinformatics) Macaulay (molecular biology, technology development), and Tunbridge (neurobiology, target identification) groups. The main aim of the project is to develop approaches to reconstruct regulatory networks at the transcript level in the human brain, assess the transcript regulation for candidate genes, and assess the impact of genetic variation on transcript regulation.

The student will work in a rapidly developing field and gain unique expertise in computational biology, large dataset analysis, genomics, transcriptomics, sequencing technologies, molecular biology, technology development, and therapeutic target identification.

The project will be conducted at the Earlham Institute, a UKRI-BBSRC research centre of excellence for bioinformatics and sequencing technology development, in close collaboration with scientists at the University of Oxford. The student will have access to training and career development opportunities at EI and on the Norwich Research Park as part of the Norwich Biosciences Doctoral Training Partnership.

References

Clark M., et al. 2020. Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain. Mol Psychiatry 25:37-47.

Mincarelli L., et al. 2020. Combined single-cell gene and isoform expression analysis in haematopoietic stem and progenitor cells. biorXiv https://doi.org/10.1101/2020.04.06.027474.

Wright D. et al. 2021. Long read sequencing reveals novel isoforms and insights into splicing regulation during cell state changes. bioRxiv https://doi.org/10.1101/2021.04.27.441628