Abstract
Isoform expression is highly cell type-specific, drives cell fate trajectories, profoundly influences drug responses and its dysregulation is a cause of disease. Despite research traditionally focusing on alternative splicing, the use of alternative transcription start sites (TSSs) and termination sites (TTSs) accounts for the majority of transcriptional diversity in humans. Yet little is known about what governs alternative TSS and TTS isoform choice. Our preliminary data show chromatin organisation, via 3D isoform-enhancer interactions, likely plays a crucial role, but no in-depth research has been done. We hypothesise that chromatin organisation is a central coordinator of isoform choice. As the brain contains the widest isoform diversity it is ideal for addressing this question. I will use experimental methods including the chromatin organisation technology patented by Prof. Malysheva, which is the only method capable of detecting isoform-level 3D chromatin organisation interactions in rare cell populations at high resolution, as well as computational methods for integrative regulatory network inference to identify the drivers of isoform choice in the major cell types of the human frontal cortex. This project will reveal the ground rules of isoform choice, which, in the long run, will be a game-changer for understanding the role of isoforms in health and disease and shift the regulatory paradigm from gene-centric to isoform-centric.
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