An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level.
An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level.
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受遗传变异影响的 BCL11A 红系增强子决定胎儿血红蛋白水平。
DOI：
10.1126/science.1242088
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发表时间：
2013-10-11
期刊：
影响因子：
--
通讯作者：
Orkin SH
中科院分区：
文献类型：
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作者：
Bauer DE;Kamran SC;Lessard S;Xu J;Fujiwara Y;Lin C;Shao Z;Canver MC;Smith EC;Pinello L;Sabo PJ;Vierstra J;Voit RA;Yuan GC;Porteus MH;Stamatoyannopoulos JA;Lettre G;Orkin SH
全基因组关联研究（GWAS）已经确定了许多与性状相关的常见遗传变异，通常定位于调控DNA。我们发现与胎儿血红蛋白（HbF）水平相关的BCL 11 A的常见遗传变异存在于由红细胞增强子染色质标记修饰的非编码序列中。精细定位揭示了一种与转录因子结合减少、BCL 11 A表达适度减少和HbF升高相关的基序破坏共同变体。周围序列在体内作为发育阶段特异性谱系限制性增强子起作用。基因组工程揭示了增强子在红系细胞而不是B淋巴细胞中对于BCL 11 A表达是必需的。这些发现说明了GWAS如何暴露对适当基因表达至关重要的因果元件内的适度影响的功能变体。我们提出GWAS标记的BCL 11 A增强子代表了β-血红蛋白病的治疗性基因组工程的有吸引力的靶标。
Genome-wide association studies (GWAS) have ascertained numerous trait-associated common genetic variants, frequently localized to regulatory DNA. We find 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 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 GWAS 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.