Zhang, Isabel; (2023) Deciphering the gene regulatory mechanism during neural progenitor cell diversification. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Coordinated temporal and spatial patterning during embryogenesis establish different cell types – neurons and glia – that comprise the nervous system. Moreover, these cells can be classified into hundreds of molecularly and functionally distinct subtypes. Here, we provide evidence that sets of global temporal transcription factors (TFs) stratify cell identity based on the developmental time at which they are generated. Our work revealed that this programme is conserved along the neuraxis. Glia, including astrocytes and oligodendrocytes, arise in a temporally regulated manner. Their production supersedes the generation of most neurons but our understanding of the gene regulatory mechanisms that control this transition is limited. Using an in vitro model, we show that the chromatin landscape in distinct ventral spinal cord neural progenitor cells (NPCs) is reorganised in a series of timed stages. Changes in chromatin accessibility and gene expression, uncover distinct dynamics. Strikingly, global temporal changes in regulatory element usage dominate domain-specific changes, suggesting a unified temporal programme of chromatin remodelling across progenitors. Analysis of accessible regions revealed TF binding motifs and footprints for novel but also known factors that are involved in gliogenesis, including NFI and SOX binding factors. These findings highlight the role of the members of these TF families in the induction of glial competency. Perturbation of NFIA/B results in the misregulation of the correctly timed transition and leads to a dramatic loss of accessibility at a subset of elements. Finally, perturbation of a library of genes using CRISPR-Cas9 during the gliogenic switch uncovered novel candidate regulators of Nfia and the induction of glial fate. Overall, integrating the chromatin accessibility, transcriptomic and perturbation data identifies new tempo- and cell-type specific gene regulatory mechanisms involved in the timing of the switch. Together, this thesis provides novel insights into how spatiotemporal gene regulatory programmes in NPCs drive cell type transitions and diversity.

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