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

被引：512

作者：

Bauer, Daniel E. ^{[1
,2
,3
]}

Kamran, Sophia C. ^{[3
,4
]}

Lessard, Samuel ^{[5
,6
]}

Xu, Jian ^{[1
,3
]}

Fujiwara, Yuko ^{[1
]}

Lin, Carrie ^{[1
]}

Shao, Zhen ^{[1
]}

Canver, Matthew C. ^{[3
]}

Smith, Elenoe C. ^{[1
]}

Pinello, Luca ^{[7
]}

Sabo, Peter J. ^{[8
,9
]}

Vierstra, Jeff ^{[8
,9
]}

Voit, Richard A. ^{[10
]}

Yuan, Guo-Cheng ^{[7
,11
]}

Porteus, Matthew H. ^{[10
]}

Stamatoyannopoulos, John A. ^{[8
,9
]}

Lettre, Guillaume ^{[5
,6
]}

Orkin, Stuart H. ^{[1
,2
,3
,4
]}

机构：

[1] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Boston, MA 02115 USA

[4] Howard Hughes Med Inst, Boston, MA 02115 USA

[5] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada

[6] Univ Montreal, Montreal, PQ H1T 1C8, Canada

[7] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA

[8] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[9] Univ Washington, Dept Med, Seattle, WA 98195 USA

[10] Stanford Univ, Dept Pediat, Palo Alto, CA 94304 USA

[11] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA

来源：

SCIENCE | 2013年 / 342卷 / 6155期

关键词：

GENOME-WIDE ASSOCIATION; SICKLE-CELL-DISEASE; HAPLOTYPE FUSION PCR; LYMPHOID DEVELOPMENT; COMMON DISEASE; GLOBIN; DNA; DISSECTION; EXPRESSION; DYNAMICS;

D O I：

10.1126/science.1242088

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：253 / 257

页数：5

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