Revealing mRNA alternative splicing complexity in the human brain
About Nicola Hall
Nicola Hall is a postdoctoral researcher at the University of Oxford in Department of Psychiatry with the Tunbridge group. She is using her background in molecular biology and RNA sequencing to investigate gene expression in the human brain. Her current work focuses on alternative splicing of the calcium channel CACNA1C, implicated in schizophrenia and bipolar disorder. Nicola completed her PhD in 2017 at the University of Oxford in the Department of Biochemistry.
Identifying the cellular pathways underlying psychiatric disorders has great potential to improve patient lives. Voltage-gated calcium channels (VGCCs), including CACNA1C, have been linked to the risk of bipolar disorder and schizophrenia, so are promising targets for new treatments. VGCCs are also important in the cardiovascular system, meaning treatments must be tissue-selective. We aim to identify brain-enriched CACNA1C isoforms as novel targets for new treatments. We used targeted long-range nanopore sequencing to characterise full length transcripts of CACNA1C in human brain and mouse brain, heart and aorta. In human we identified >250, and in mouse >190, mRNA isoforms, exons and splice junctions; including many predicted to modulate protein function. In mice, splicing was clearly tissue-specific, and we expect that this underlying principle of tissue-specific splicing will be conserved between mice and humans. Our data show that splicing of CACNA1C in human brain is far more diverse than is currently appreciated. This information will be critical to reveal pathophysiological mechanisms, and to identify brain-enriched VGCC isoforms that may be novel targets for new psychiatric treatments.