Abstract
Adult neurogenesis plays an essential role in normal cognitive function including in memory formation, learning, pattern separation and mood regulation and is disrupted in neurodegenerative disorders. Adult neurogenesis primarily occurs in two regions of the adult brain: the dentate gyrus (DG) of the hippocampus, and the subventricular zone. In the DG, neural stem cells slowly give rise to neural intermediate progenitor cells, neuroblasts and ultimately new neurons. Intriguingly, NSCs are thought to be almost entirely quiescent, expressing no markers for active proliferation, with the detection of any proliferating cells often proving difficult. Yet, NSCs are maintained throughout adulthood. This apparent contradiction emphasises our current lack of understanding of the regulatory mechanisms underlying NSC transition from a state of quiescence to a state of proliferation. It is vital that we understand these processes, and identify the key factors regulating it, so that we know how exactly and why neurogenesis is impaired in disease, and how we can intervene to treat it.
Changes in the 3D structure of chromatin are essential for coordinating the transition from quiescence to self-renewal in other stem cell populations including in hematopoietic stem cells. Yet no study has ever investigated the role of the changing 3D structure of chromatin in the NSCs in the DG. This is a significant shortcoming as changes in chromatin organisation often precede transcriptional changes, with gene promoters interacting with 'primed' or 'poised' enhancer regulatory elements prior to activation. I therefore hypothesise that NSCs exist in functionally distinct states, distinguishable at the level of 3D chromatin organisation, and that changes in chromatin organisation coordinate the transition from quiescence to self-renewal, shaping cell fate trajectories during adult neurogenesis in the DG.
To investigate these hypotheses I propose the first ever study of chromatin organisation in the human DG. For this we will develop a novel technology (scSPRITE-IP) for profiling multiway chromatin hubs at high-resolution in single cells and apply it to detect the regulatory chromatin interactions governing the NSC transition from quiescence to self-renewal state. Importantly, to understand adult neurogenesis, regulated at so many intrinsic and extrinsic levels, a holistic approach which can integrate information across scales and modalities must be taken. Therefore, we will integrate the scSPRITE-IP data with single-cell gene expression, chromatin accessibility and disease risk-variants (GWAS) data in a novel bespoke computational inference framework and identify key factors regulating adult neurogenesis.
Our group's dual expertise in the development of novel experimental methods for profiling chromatin organisation in rare cell populations, as well as development of multimodal, integrative network inference methods and statistical analysis tools is essential to the success of this project and ensures its success. Through the development of novel experimental and computational approaches this highly innovative proposal carries transformative potential both in the field of neurogenesis and well beyond stem cell research in the brain, enabling the advance of research into cell fate acquisition in other tissues and organisms, in health and disease.
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