Erythroid GATA1 function revealed by genome-wide analysis of transcription factor occupancy, histone modifications, and mRNA expression
Erythroid GATA1 function revealed by genome-wide analysis of transcription factor occupancy, histone modifications, and mRNA expression
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DOI：
10.1101/gr.098921.109
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发表时间：
2009-12-01
期刊：
影响因子：
7
通讯作者：
Hardison, Ross C.
中科院分区：
文献类型：
--
作者：
Cheng, Yong;Wu, Weisheng;Hardison, Ross C.
转录因子GATA1在红细胞发育过程中调控着广泛的基因激活和抑制程序。然而，相关机制，包括远端与近端顺式调控元件的作用、与其他转录因子的共占位以及组蛋白修饰的影响，人们知之甚少。我们在一个Gata1基因敲除的成红细胞系中对这些问题进行了全基因组研究，该细胞系在GATA1依赖的终末成熟过程中，在恢复GATA1后鉴定出2616个GATA1响应基因和15360个GATA1占据的DNA片段。几乎所有被占据的DNA片段在典型的GATA结合基序周围都有高水平的H3K4单甲基化和低水平的H3K27me3，无论附近的基因是被诱导还是被抑制。被诱导的基因往往在靠近转录起始位点（最常见于第一内含子）处被GATA1结合，具有多个也被TAL1结合的GATA1占据片段，并且在GATA1结合位点基序上显示出进化限制。相比之下，被抑制的基因距离GATA1占据片段更远，并且一部分基因在转录起始位点处显示出TAL1占位减少和H3K27me3增加。我们的数据通过定义一组新的靶基因并确定整个基因组中顺式调控元件的空间分布，扩展了GATA1在红细胞生成中的作用范围。此外，我们开始建立区分GATA1在特定靶基因上激活与抑制的功能标准和机制。更广泛地说，这些研究阐明了一个“主调节因子”转录因子如何通过一系列DNA和蛋白质相互作用来协调组织分化。
The transcription factor GATA1 regulates an extensive program of gene activation and repression during erythroid development. However, the associated mechanisms, including the contributions of distal versus proximal cis-regulatory modules, co-occupancy with other transcription factors, and the effects of histone modifications, are poorly understood. We studied these problems genome-wide in a Gata1 knockout erythroblast cell line that undergoes GATA1-dependent terminal maturation, identifying 2616 GATA1-responsive genes and 15,360 GATA1-occupied DNA segments after restoration of GATA1. Virtually all occupied DNA segments have high levels of H3K4 monomethylation and low levels of H3K27me3 around the canonical GATA binding motif, regardless of whether the nearby gene is induced or repressed. Induced genes tend to be bound by GATA1 close to the transcription start site ( most frequently in the first intron), have multiple GATA1-occupied segments that are also bound by TAL1, and show evolutionary constraint on the GATA1-binding site motif. In contrast, repressed genes are further away from GATA1-occupied segments, and a subset shows reduced TAL1 occupancy and increased H3K27me3 at the transcription start site. Our data expand the repertoire of GATA1 action in erythropoiesis by defining a new cohort of target genes and determining the spatial distribution of cis-regulatory modules throughout the genome. In addition, we begin to establish functional criteria and mechanisms that distinguish GATA1 activation from repression at specific target genes. More broadly, these studies illustrate how a "master regulator'' transcription factor coordinates tissue differentiation through a panoply of DNA and protein interactions.