DiMeN Doctoral Training Partnership: Dissection of the chromatin landscape of normal hematopoiesis and its disruption in immunodeficiencies

Changes in chromatin configuration play an essential role in development and differentiation of cells. These chromatin state dynamics lead to a great variety of epigenomes. Generally, individuals will be characterized by one genome, but by as many epigenomes as there are cell types. Haematopoiesis is a dynamic process in which haematopoietic stem cells give rise many different cell types, including lymphocytes, neutrophils, monocytes, platelets or erythrocytes. The contribution of epigenomic changes during haematopoietic differentiation to these alternative cell phenotypes is not well understood. Primary immunodeficiencies provide model systems in which to explore this relationship.

In this project, the PhD student will first mine publicly available epigenomic data from healthy individuals (from http://ihec-epigenomes.org/ and other sources) to identify regions with differential epigenetic states among different immune cell types. This atlas of chromatin determinant regions will be then used as a reference to investigate possible epigenomic alterations that are associated with different primary immunodeficiencies. For this, the student will generate chromatin accessibility maps by ATAC-seq from specific patient cell populations in the laboratory of the primary supervisor. Under the supervision of both supervisors, the student will analyse the epigenomic profiles of immature haematopoietic precursors to identify altered local chromatin configuration that could contribute to the cellular deficiencies in each patient. In summary, this work will exploit the available epigenomic resources to add mechanistic insights in immunodeficiencies, and in turn indicate critical aspects of epigenomic reprogramming that contribute to immune cell development.