Journal
SCIENCE
Volume 342, Issue 6155, Pages 253-257Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1242088
Keywords
-
Categories
Funding
- Doris Duke Charitable Foundation [2009089]
- Canadian Institute of Health Research [123382]
- Amon Carter Foundation
- Hyundai Hope on Wheels
- NIH [U54HG004594, U54HG007010, R01HL032259, P01HL032262, P30DK049216]
- Lucille Packard Foundation
- National Institute of Diabetes and Digestive and Kidney Diseases Career Development [K08DK093705]
Ask authors/readers for more resources
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 beta-hemoglobinopathies.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available