Transcriptional silencing of γ-globin by BCL11A involves long-range interactions and cooperation with SOX6
Transcriptional silencing of γ-globin by BCL11A involves long-range interactions and cooperation with SOX6
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DOI：
10.1101/gad.1897310
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发表时间：
2010-04-15
影响因子：
10.5
通讯作者：
Orkin, Stuart H.
中科院分区：
文献类型：
--
作者：
Xu, Jian;Sankaran, Vijay G.;Orkin, Stuart H.
从人类胎儿（γ）到成人（β）血红蛋白的发育转换代表了发育基因调控的临床重要实例。转录因子BCL 11 A是γ-珠蛋白沉默和血红蛋白转换的中心介质。在这里，我们确定染色质占用BCL 11 A在人类β-珠蛋白基因座和其他基因组区域在体内高分辨率染色质免疫沉淀（ChIP）芯片分析。BCL 11 A结合上游基因座控制区（LCR）、ε-珠蛋白以及γ-珠蛋白和δ-珠蛋白基因之间的基因间区域。染色体构象捕获（3C）测定显示BCL 11 A通过调节染色体环形成来重构β-珠蛋白簇。我们还表明，BCL 11 A和HMG盒的转录因子SOX 6在红细胞成熟过程中的物理和功能相互作用。BCL 11 A和SOX 6与GATA 1一起沿着占据人β-珠蛋白簇，并在成人红系祖细胞中协同沉默γ-珠蛋白转录。这些发现共同表明，γ-珠蛋白基因的转录沉默BCL 11 A涉及与SOX 6的远程相互作用和合作。我们的研究结果提供了深入了解BCL 11 A的行动机制和新的线索，发育基因调控程序的功能在β-珠蛋白基因座。
The developmental switch from human fetal (gamma) to adult (beta) hemoglobin represents a clinically important example of developmental gene regulation. The transcription factor BCL11A is a central mediator of gamma-globin silencing and hemoglobin switching. Here we determine chromatin occupancy of BCL11A at the human beta-globin locus and other genomic regions in vivo by high-resolution chromatin immunoprecipitation (ChIP)-chip analysis. BCL11A binds the upstream locus control region (LCR), epsilon-globin, and the intergenic regions between gamma-globin and delta-globin genes. A chromosome conformation capture (3C) assay shows that BCL11A reconfigures the beta-globin cluster by modulating chromosomal loop formation. We also show that BCL11A and the HMG-box-containing transcription factor SOX6 interact physically and functionally during erythroid maturation. BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors. These findings collectively demonstrate that transcriptional silencing of gamma-globin genes by BCL11A involves long-range interactions and cooperation with SOX6. Our findings provide insight into the mechanism of BCL11A action and new clues for the developmental gene regulatory programs that function at the beta-globin locus.