Identification of sequences and factors required for HbF repression

Boston Children'S Hospital, Boston MA

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Abstract

? DESCRIPTION (provided by applicant): The level of fetal hemoglobin (HbF) is a key modifier of the clinical severity of the ?-hemoglobin disorders sickle cell disease and ?-thalassemia. The goal of this proposal is to identify mechanisms that regulate HbF level and could serve as rational targets for efforts to re-induce HbF for the ?-hemoglobin disorders. Genome- wide association studies (GWASs) have identified BCL11A as a critical HbF-associated locus. Functional studies have demonstrated that BCL11A is a bona fide repressor of ?-globin transcription. Naturally occurring common genetic variation modulates an erythroid-specific enhancer of BCL11A. Our prior studies identified the GWAS-marked erythroid enhancer of BCL11A as the substrate for common genetic variation associated with HbF level. Genome editing has revealed critical sequences within this enhancer required for HbF repression in the adult stage. I hypothesize that these sequences recruit critical trans-acting factors, which themselves are required for suppressing HbF levels. In addition, I hypothesize that other critical sequences at the BCL11A and HBS1L-MYB loci are required to repress HbF in the adult-stage. To test these hypotheses, I will: (1) utilize a high-resolution, high-throughput genome editing approach to identify non-coding sequences at BCL11A and HBS1L-MYB associated with HbF level; and (2) define trans-acting factors that physically and functionally interact with critical on-coding sequences at BCL11A and HBS1L-MYB. I expect that accomplishment of these aims will not only deepen our current understanding of cis- and trans-acting determinants of developmental regulation of globin gene expression but also yield novel insights to guide therapeutic efforts for HbF re-induction.