Characterizing the role of BCL11A in hematopoietic development and functions

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DESCRIPTION (provided by applicant): Analysis of the molecular mechanisms regulating human hemoglobin switching is critical to the development of target-based therapies for β-hemoglobin disorders, including sickle cell disease and β-thalassemias. Reactivation of fetal hemoglobin (HbF) in adults lessens the severity of these conditions. We recently showed that the transcription factor BCL11A is a direct regulator of HbF switching and silencing. BCL11A was initially identified as a candidate regulator of HbF through genome-wide association studies (GWAS). Knockout of BCL11A in mice impairs developmental HbF silencing in adult erythroid cells. Inactivation of BCL11A in humanized SCD mice corrects the hematologic and pathologic defects through high-level HbF induction. Thus, BCL11A represents the first genetically and functionally validated regulator of HbF silencing in man. To further evaluate BCL11A as a practicable therapeutic target, it is important to examine several criteria, including effects of BCL11A loss on non-globin genes in red cells and impact outside the erythroid lineage. The objective of this application is to analyze the role of BCL11A in normal hematopoiesis and investigate the molecular mechanisms underlying its cell-type- specific functions. I hypothesize that BCL11A interacts with different partner proteins and targets distinct chromatin regions depending on the cellular context. To test this hypothesis, I will : 1, Define the role of BCL11A during normal hematopoiesis in conditional knockout mouse models; and 2, Characterize BCL11A-centered transcriptional networks in erythroid and lymphoid cells by comparative genomic and proteomic analyses. I expect that findings from this study not only will reveal general features of cell- type-specific regulation mediated by a disease-associated hematopoietic regulator, but provide the necessary foundation for designing therapeutic strategies to target BCL11A for HbF induction in patients with the major hemoglobin disorders.