Embryonic blood specification: Unravelling transcriptional and chromatin-based mechanisms in early haematopoiesis

Haematopoiesis is a tightly coordinated process that forms and maintains all blood cells. Intriguingly, haematopoietic differentiation during embryonic development is distinct from adult haematopoiesis. Whereas adult haematopoiesis is maintained by haematopoietic stem cells (HSCs) with self-renewal and multi-lineage differentiation capacity, the first arising blood lineages in the embryo are generated by transient lineage-restricted haematopoietic progenitor cells (HPCs), independently of bona-fide HSCs. This
early haematopoietic output is not only essential for foetal survival but also impacts the adult, as specialised blood lineages arise exclusively in this developmental time window and are maintained throughout life. While molecular mechanisms in adult haematopoiesis have been extensively catalogued, the processes regulating early lineage-restricted blood development remain largely unexplored. I aim to investigate the contribution of transcriptional and chromatin-based mechanisms during early haematopoietic differentiation. Towards this, I will combine a mouse embryonic stem cell-based differentiation model that closely recapitulates embryonic blood development with large-scale, targeted CRISPR-Cas9 screens, in order to identify the transcription factors and chromatin-modifiers essential for lineage choice during early haematopoiesis. Subsequent characterisation of the identified factors using functional genomics assays will provide important insights into their function during early haematopoiesis.
This strategy, in combination with in vitro terminal differentiation and in vivo reconstitution experiments, will further determine how the adult-like haematopoietic programme is actively repressed in early haematopoiesis through transcriptional and/or chromatin-mediated silencing. Collectively, I aim to unravel the molecular mechanisms governing key developmental principles in early haematopoiesis, thus gaining novel insights on this essential developmental process.