作者
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 Stamatoyannopoulos, Guillaume Lettre, Stuart H Orkin
发表日期
2013/10/11
期刊
Science
卷号
342
期号
6155
页码范围
253-257
出版商
American Association for the Advancement of Science
简介
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 …
引用总数
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