An Erythroid Enhancer of BCL11A Subject to Genetic Variation Determines Fetal Hemoglobin Level

• DOI: 10.1126/science.1242088
• Publication Date: 2013-10-10T18:50:09Z
• Authors: Daniel E. Bauer; Sophia C. Kamran; Samuel Lessard; Jian Xu; Yuko Fujiwara; Carrie Lin; Zhen Shao; Matthew C. Canver; Elenoe C. Smith; Luca Pinello; Peter J. Sabo; Jeff Vierstra; Richard A. Voit; Guo-Cheng Yuan; Matthew H. Porteus; John A. Stamatoya...; Guillaume Lettre; Stuart H. Orkin
• Keywords: Genome-wide Association Study

Genome-wide association studies (GWASs) have ascertained numerous trait-associated common genetic variants, frequently localized to regulatory DNA. We found that variation at BCL11A associated with fetal hemoglobin (HbF) level lies in noncoding sequences decorated by an erythroid enhancer chromatin signature. Fine-mapping uncovers a motif-disrupting variant reduced transcription factor (TF) binding, modestly diminished expression, and elevated HbF. The surrounding function vivo as developmental stage-specific, lineage-restricted enhancer. Genome engineering reveals the is required but not B-lymphoid cells for expression. These findings illustrate how GWASs may expose functional variants of modest impact within causal elements essential appropriate gene propose GWAS-marked represents attractive target therapeutic genome β-hemoglobinopathies.