Transcriptional and chromatin-based mechanisms in developmental haematopoiesis
We study molecular events that impact blood emergence during mammalian development and how genetic perturbations influence blood lineage specification in the embryo.
By using an embryonic stems cell-derived differentiation model that closely resembles murine blood development in combination with targeted, large-scale CRISPR-Cas9 screens, we aim to identifying novel molecular players regulating early blood differentiation.
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.
By combining our embryonic stem cell-derived differentiation system with large-scale targeted CRISPR-Cas9 screens, we aim to fill this gap. Our subsequent molecular analysis of identified candidate genes using functional genomics assays will provide important insights into their function during early haematopoiesis.
We employ various experimental and high-throughput techniques including high-dimensional flow cytometry, (epi)genome engineering, genome-wide chromatin accessibility and immunoprecipitation assays, single-cell gene expression measurements and computational analysis of large-scale data sets.
Ultimately, understanding the basis of transcriptional and chromatin-based control in early haematopoiesis is of key relevance as misregulations of haematopoietic differentiation are implicated in numerous human diseases, including cancer, infections and autoimmune diseases.