Distinct Ldb1/NLI complexes orchestrate γ-globin repression and reactivation through ETO2 in human adult erythroid cells
Distinct Ldb1/NLI complexes orchestrate γ-globin repression and reactivation through ETO2 in human adult erythroid cells
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DOI：
10.1182/blood-2011-06-363101
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发表时间：
2011-12-01
期刊：
影响因子：
20.3
通讯作者：
Dean, Ann
中科院分区：
文献类型：
--
作者：
Kiefer, Christine M.;Lee, Jongjoo;Dean, Ann
Ldb 1/加塔-1/TAL 1/LMO 2复合物介导成年小鼠红系细胞中β-珠蛋白基因座控制区（LCR）和基因之间的长程相互作用，但该复合物是否介导其他发育阶段或人类细胞中的染色质相互作用尚不清楚。我们研究了NLI（Ldb 1同系物）复合物的占用率和染色质构象的β-珠蛋白基因座在人类红系细胞。除了LCR之外，我们还在BGL 3（一种基因间RNA转录物）序列内的（A）γ-珠蛋白基因下游位点处发现了稳健的NLI复合物占据。在主要转录β-珠蛋白的细胞中，BGL 3不被转录，BGL 3序列被NLI核心复合物成员、辅阻遏物ETO 2和γ-珠蛋白阻遏物BCL 11 A占据。LCR和β-珠蛋白基因在这些细胞中建立了接近性。相反，当γ-珠蛋白转录在这些细胞中被重新激活时，ETO 2参与BGL 3的NLI复合物减少，BCL 11 A占据也是如此，BGL 3和γ-珠蛋白都被转录。在这些细胞中，BGL 3/γ-珠蛋白区域和LCR之间的接近被建立。我们的结论是，替代NLI复合物介导γ-珠蛋白转录或沉默通过长距离LCR相互作用，涉及非编码RNA转录的基因间位点，ETO 2是这个过程中的关键。（血。2011;118（23）：6200-6208）
The Ldb1/GATA-1/TAL1/LMO2 complex mediates long-range interaction between the beta-globin locus control region (LCR) and gene in adult mouse erythroid cells, but whether this complex mediates chromatin interactions at other developmental stages or in human cells is unknown. We investigated NLI (Ldb1 homolog) complex occupancy and chromatin conformation of the beta-globin locus in human erythroid cells. In addition to the LCR, we found robust NLI complex occupancy at a site downstream of the (A)gamma-globin gene within sequences of BGL3, an intergenic RNA transcript. In cells primarily transcribing beta-globin, BGL3 is not transcribed and BGL3 sequences are occupied by NLI core complex members, together with corepressor ETO2 and by gamma-globin repressor BCL11A. The LCR and beta-globin gene establish proximity in these cells. In contrast, when gamma-globin transcription is reactivated in these cells, ETO2 participation in the NLI complex at BGL3 is diminished, as is BCL11A occupancy, and both BGL3 and gamma-globin are transcribed. In these cells, proximity between the BGL3/gamma-globin region and the LCR is established. We conclude that alternative NLI complexes mediate gamma-globin transcription or silencing through long-range LCR interactions involving an intergenic site of non-coding RNA transcription and that ETO2 is critical to this process. (Blood. 2011;118(23):6200-6208)