Project description
Molecular mechanisms and dynamics of in vivo glia-to-neuron reprogramming
Recent studies have demonstrated the possibility of direct reprogramming of brain glia into neurons in vivo paving the way for future regeneration of neurons damaged by injury or disease. However, the molecular underpinnings of glia-to-neuron conversion are still poorly understood. Funded by the Marie Skłodowska-Curie Actions programme, Neuro-ReprOmics will address the question of how neurogenic reprogramming factors remodel gene expression programmes during glial cell conversion into induced neurons. The study will utilise defined combinations of reprogramming factors leading to the generation of distinct types of neurons as well as single-cell RNA and assay for transposase-accessible chromatin sequencing to elucidate the reprogramming trajectories, mechanisms, and epigenomic changes that drive the process.
Objective
Direct lineage reprogramming of cell identity in the nervous system offers the prospect of remodelling diseased brain circuits. Recent years have provided evidence for the possibility of converting brain glia into neurons in vivo. This may eventually allow to regenerate neurons that have degenerated as a consequence of injury or disease. Yet, the process by which glial cells give up their original identity and adopt a neuronal fate remains by large enigmatic. Moreover, the knowledge of molecular underpinnings of glia-to-neuron conversion is lacunary and virtually nothing is known about the process in vivo. The Berninger laboratory has discovered specific cocktails of reprogramming factors that gives rise to induced neurons in the mouse cerebral cortex, with some cells adopting hallmark features of fast-spiking, parvalbumin-expressing interneurons, a neuronal subtype that is highly vulnerable in neuropsychiatric and neurological disorders. The aim of my project addresses the question of how these neurogenic reprogramming factors remodel gene expression programs as glial cells convert into neurons. Thus, I will utilize defined combinations of reprogramming factors leading to the generation the distinct types of neurons to elucidate how and when the reprogramming trajectories diverge. Towards this end, I will establish single cell RNA sequencing as well as scATAC-seq from cells undergoing conversion in vivo to uncover the transcriptomic and epigenomic changes that drive this process. The outcome of this study is twofold, as this will break new ground in our understanding of how transcription factors can overcome existing cell-specific gene expression programs to induce new cellular identities, and at the same time identify new molecular handles for rendering reprogrammed cells more similar to their endogenous counterparts in an attempt to improve the prospects of using this strategy for brain repair.
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Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
WC2R 2LS London
United Kingdom