SCL and associated proteins distinguish active from repressive GATA transcription factor complexes
SCL and associated proteins distinguish active from repressive GATA transcription factor complexes
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DOI：
10.1182/blood-2008-07-169417
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发表时间：
2009-03-05
期刊：
影响因子：
20.3
通讯作者：
Blobel, Gerd A.
中科院分区：
文献类型：
--
作者：
Tripic, Tamara;Deng, Wulan;Blobel, Gerd A.
加塔-1通过激活和抑制基因转录来控制造血发育，但指定这些相反活性的体内机制尚不清楚。通过检测条件性红细胞拯救系统中加塔-1相关蛋白复合物的组成以及通过使用平铺阵列，我们在所有检测的正作用加塔-1结合元件中检测到SCL/TAL 1、LMO 2、Ldb 1、E2 A复合物。类似地，SCL复合物存在于巨核细胞和肥大细胞中的所有活化加塔元件处。与此形成鲜明对比的是，在加塔-1作为阻遏物发挥功能的位点，SCL复合物被耗尽。SCL的DNA结合缺陷形式与活性加塔元件的子集保持关联，表明加塔-1是SCL募集的关键决定因素。LMO 2的敲低选择性地削弱加塔-1的激活而不是阻遏。ETO-2是一种具有转录抑制潜力的SCL相关蛋白，也不存在于加塔-1抑制基因中，但与SCL不同，ETO-2不能在加塔-1激活基因中积累。总之，这些研究确定SCL复合物是多种加塔-1调节的造血细胞谱系中加塔-1活性阳性的关键和一致的决定因素。（血。2009; 113：2191-2201）
GATA-1 controls hematopoietic development by activating and repressing gene transcription, yet the in vivo mechanisms that specify these opposite activities are unknown. By examining the composition of GATA-1-associated protein complexes in a conditional erythroid rescue system as well as through the use of tiling arrays we detected the SCL/TAL1, LMO2, Ldb1, E2A complex at all positively acting GATA-1-bound elements examined. Similarly, the SCL complex is present at all activating GATA elements in megakaryocytes and mast cells. In striking contrast, at sites where GATA-1 functions as a repressor, the SCL complex is depleted. A DNA-binding defective form of SCL maintains association with a subset of active GATA elements indicating that GATA-1 is a key determinant for SCL recruitment. Knockdown of LMO2 selectively impairs activation but not repression by GATA-1. ETO-2, an SCL-associated protein with the potential for transcription repression, is also absent from GATA-1-repressed genes but, unlike SCL, fails to accumulate at GATA-1 activated genes. Together, these studies identify the SCL complex as a critical and consistent determinant of positive GATA-1 activity in multiple GATA-1-regulated hematopoietic cell lineages. (Blood. 2009; 113: 2191-2201)