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

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Bibliographic Details
Title:	An Erythroid Enhancer of BCL11A Subject to Genetic Variation Determines Fetal Hemoglobin Level.
Authors:	Bauer, Daniel E., Kamran, Sophia C., Lessard, Samuel, Jian Xu, Yuko Fujiwara, Carrie Lin, Zhen Shao, Canver, Matthew C., Smith, Elenoe C., Pinello, Luca, Sabo, Peter J., Vierstra, Jeff, Voit, Richard A., Guo-Cheng Yuan, Porteus, Matthew H., Stamatoyannopoulos, John A., Lettre, Guillaume, Orkin, Stuart H.
Source:	Science (pre-March 2025). 10/11/2013, Vol. 342 Issue 6155, preceding p253-257. 6p.
Subjects:	Hemoglobinopathy, Erythrocyte membranes, Transcription factors, Fetus, Genetics, Chromatin, Gene expression, B cells, Health
Abstract:	Genome-wide association studies (GWASs) have ascertained numerous trait-associated common genetic variants, frequently localized to regulatory DNA. We found that common genetic 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 common variant associated with reduced transcription factor (TF) binding, modestly diminished BCL11A expression, and elevated HbF. The surrounding sequences function in vivo as a developmental stage-specific, lineage-restricted enhancer. Genome engineering reveals the enhancer is required in erythroid but not B-lymphoid cells for BCL11A expression. These findings illustrate how GWASs may expose functional variants of modest impact within causal elements essential for appropriate gene expression. We propose the GWAS-marked BCL11A enhancer represents an attractive target for therapeutic genome engineering for the b-hemoglobinopathies. [ABSTRACT FROM AUTHOR]
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Database:	Psychology and Behavioral Sciences Collection

Description
Abstract:	Genome-wide association studies (GWASs) have ascertained numerous trait-associated common genetic variants, frequently localized to regulatory DNA. We found that common genetic 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 common variant associated with reduced transcription factor (TF) binding, modestly diminished BCL11A expression, and elevated HbF. The surrounding sequences function in vivo as a developmental stage-specific, lineage-restricted enhancer. Genome engineering reveals the enhancer is required in erythroid but not B-lymphoid cells for BCL11A expression. These findings illustrate how GWASs may expose functional variants of modest impact within causal elements essential for appropriate gene expression. We propose the GWAS-marked BCL11A enhancer represents an attractive target for therapeutic genome engineering for the b-hemoglobinopathies. [ABSTRACT FROM AUTHOR]
ISSN:	00368075
DOI:	10.1126/science.1242088