An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level

By Daniel E. Bauer, S. Kamran, S. Lessard, Jian Xu, Y. Fujiwara, Carrie Lin, Zhen Shao, Matthew C. Canver, Elenoe C Smith, Luca Pinello and 8 more. Science, 2013

640 citations recorded by the source corpus.

BCL11A Variants Recent chromatin mapping data have suggested that trait-associated variants often mark regulatory DNA. However, there has been little rigorous experimental investigation of regulatory variation. Bauer et al. (p. 253; see the Perspective by Hardison and Blobel) performed an in-depth study of the BCL11A fetal hemoglobin-associated locus. The trait-associated variants revealed a chromatin signature that enhanced erythroid development. The enhancer was required for erythroid expression of BCL11A and thus for globin gene expression. Fine-mapping reveals a promising therapeutic target for genome engineering in the β-hemoglobinopathies. [Also see Perspective by Hardison and Blobel] 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 β-hemoglobinopathies.

Subfields: Genetics, Molecular Biology, Pediatrics, Perinatology and Child Health

View Paper: https://www.semanticscholar.org/paper/2845316815fa241ea105cf77d04cc6906bf4c64b

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In Genetics

1. Bogdan Pasaniuc
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4. Chris Wallace
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1. Eleazar Eskin
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Citations in the corpus

• Identifying Causal Variants at Loci with Multiple Signals of Association (2014, background): “Over the past few years, GWAS have identified hundreds of genetic loci harboring genetic variation affecting disease risk for hundreds of common diseases (Bauer et al. 2013; Coram et al. 2013; Diogo et al. 2013; Gong et al. 2013; Marigorta and Navarro 2013; Peters et al. 2013; Wu et al. 2013).”
• Beyond GWASs: illuminating the dark road from association to function. (2013, background): “Fetal hemoglobin levels 2p16 rs1427407, rs7606173 BCL11A (MIM 606557) 3C, ChIP-seq, reporter assays, transgenic mouse models, allele-specific expression, TALENs Bauer et al.(5)”