A crucial role for the ubiquitously expressed transcription factor Sp1 at early stages of hematopoietic specification.
A crucial role for the ubiquitously expressed transcription factor Sp1 at early stages of hematopoietic specification.
复制标题
DOI：
10.1242/dev.106054
复制
发表时间：
2014-06
期刊：
影响因子：
--
通讯作者：
Bonifer C
中科院分区：
文献类型：
--
作者：
Gilmour J;Assi SA;Jaegle U;Kulu D;van de Werken H;Clarke D;Westhead DR;Philipsen S;Bonifer C
哺乳动物的发育受组织特异性和普遍表达的转录因子（如Sp1）的相互作用调节。Sp1基因敲除小鼠在子宫内死亡，具有多种表型畸变，但这种分化失败的潜在分子机制尚不清楚。在这里，我们使用条件性基因敲除小鼠以及小鼠ES细胞的分化作为解决这个问题的模型。为此，我们研究了分化潜力，全球基因表达模式和Sp1野生型和Sp1缺陷细胞代表造血的不同阶段的Sp1靶区域。Sp1−/−细胞在血细胞发育的大多数胚胎阶段都能发育，但不能完成终末分化。当Sp1在以后的发育阶段被敲除时，没有看到这种完全分化的失败。对于大多数Sp1靶基因和非靶基因，基因表达不受Sp1失活的影响。然而，Cdx基因和多个Hox基因是Sp1的阶段特异性靶点，并且在早期阶段下调。因此，参与造血特化的基因表达逐渐失调。我们的工作表明，早期缺乏活性Sp1设置级联运动，最终在终端造血分化失败，并强调组织特异性基因调控的普遍表达的转录因子的作用。此外，我们的全球并排分析的转录网络扰动的反应，揭示了新的光造血规范的监管层次。
Mammalian development is regulated by the interplay of tissue-specific and ubiquitously expressed transcription factors, such as Sp1. Sp1 knockout mice die in utero with multiple phenotypic aberrations, but the underlying molecular mechanism of this differentiation failure has been elusive. Here, we have used conditional knockout mice as well as the differentiation of mouse ES cells as a model with which to address this issue. To this end, we examined differentiation potential, global gene expression patterns and Sp1 target regions in Sp1 wild-type and Sp1-deficient cells representing different stages of hematopoiesis. Sp1−/− cells progress through most embryonic stages of blood cell development but cannot complete terminal differentiation. This failure to fully differentiate is not seen when Sp1 is knocked out at later developmental stages. For most Sp1 target and non-target genes, gene expression is unaffected by Sp1 inactivation. However, Cdx genes and multiple Hox genes are stage-specific targets of Sp1 and are downregulated at an early stage. As a consequence, expression of genes involved in hematopoietic specification is progressively deregulated. Our work demonstrates that the early absence of active Sp1 sets a cascade in motion that culminates in a failure of terminal hematopoietic differentiation and emphasizes the role of ubiquitously expressed transcription factors for tissue-specific gene regulation. In addition, our global side-by-side analysis of the response of the transcriptional network to perturbation sheds a new light on the regulatory hierarchy of hematopoietic specification.
登录
查看更多内容
影响因子：
64.8
作者：
Chen, Michael J.;Yokomizo, Tomomasa;Zeigler, Brandon M.;Dzierzak, Elaine;Speck, Nancy A.
通讯作者：
Speck, Nancy A.
影响因子：
20.3
作者：
Mikkola, HKA;Fujiwara, Y;Orkin, SH
通讯作者：
Orkin, SH
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
DOI：
10.1111/j.1749-6632.2012.06625.x
发表时间：
2012-01-01
期刊：
HEMATOPOIETIC STEM CELLS VIII
影响因子：
--
作者：
Lengerke, Claudia;Daley, George Q.
通讯作者：
Daley, George Q.
影响因子：
8
作者：
Clarke, D;Vegiopoulos, A;Frampton, J
通讯作者：
Frampton, J