Elucidate the role of higher-order chromatin organization during terminal differentiation in mouse erythropoiesis

Project Summary: It is widely appreciated that erythropoiesis serves as an excellent model for studying modifications in chromatin organization and resultant gene expression patterns within identical cells. This process involves significant chromatin reshuffling and a loss of topologically associating domains, ultimately leading to global transcriptional silencing upon terminal erythroid differentiation. Despite these insights, the precise structural changes underpinning the distinct gene expression seen in terminally differentiated erythroid cells remain enigmatic. Therefore, there is an urgent need to elucidate the detailed molecular mechanisms governing chromatin architecture modifications during erythroid terminal differentiation, to enhance our understanding of erythropoiesis-related diseases, particularly anemia. The overall objective of the proposed research is to decipher the roles and interactions of erythroid-specific transcription factors and chromatin structural proteins during erythropoiesis, defining how they lead from cellular expansion to differentiation. Our central hypothesis posits that erythroid-specific transcription factors and architectural proteins direct modifications in chromatin organization integral to erythroid terminal differentiation. To this end the specific aims of this proposal seek to combine functional studies with state-of-the-art-multi-omics approaches to: 1) Test the functional role of architectural proteins during terminal differentiation in mouse erythropoiesis 2) Identify and characterize chromatin re-organization events during terminal differentiation 3) Identifying the molecular mechanisms underlying the 3D chromatin changes during erythropoiesis