Genomic targets of Brachyury (T) in differentiating mouse embryonic stem cells.
Genomic targets of Brachyury (T) in differentiating mouse embryonic stem cells.
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DOI：
10.1371/journal.pone.0033346
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Smith JC
中科院分区：
文献类型：
--
作者：
Evans AL;Faial T;Gilchrist MJ;Down T;Vallier L;Pedersen RA;Wardle FC;Smith JC
T-box转录因子Brachyury（T）是脊椎动物胚胎后中胚层和脊索形成所必需的。在青蛙和斑马鱼中的工作已经确定了Brachyury的一些直接基因组靶点，但对小鼠中的Brachyury靶点知之甚少。在这里，我们使用染色质免疫沉淀和小鼠启动子微阵列，以确定目标的Brachyury在胚胎体形成的分化小鼠ES细胞。我们确定的目标是丰富的序列特异性DNA结合蛋白，并包括信号转导途径的组件，直接细胞的命运在原始条纹和尾芽的早期胚胎。其中一些靶点的表达，如Axin 2，Fgf 8和Wnt 3a，在Brachyury突变胚胎中下调，我们证明它们也是人类Brachyury靶点。令人惊讶的是，我们没有观察到典型的T结构域DNA结合序列5′-TCACACCT-3′在大多数Brachyury靶基因附近的富集。相反，我们已经确定了一个（AC）n重复序列，这是保守的大鼠，但不是在人类，斑马鱼或爪蟾。我们不了解这个序列的意义，但推测它增强了啮齿动物中Brachyury靶基因调控区的转录因子结合。我们的工作确定了早期小鼠胚胎中胚层形成的关键调节因子的基因组靶点，从而为Brachyury驱动的遗传调控网络提供了见解，并使我们能够比较Brachyury在不同物种中的功能。
The T-box transcription factor Brachyury (T) is essential for formation of the posterior mesoderm and the notochord in vertebrate embryos. Work in the frog and the zebrafish has identified some direct genomic targets of Brachyury, but little is known about Brachyury targets in the mouse. Here we use chromatin immunoprecipitation and mouse promoter microarrays to identify targets of Brachyury in embryoid bodies formed from differentiating mouse ES cells. The targets we identify are enriched for sequence-specific DNA binding proteins and include components of signal transduction pathways that direct cell fate in the primitive streak and tailbud of the early embryo. Expression of some of these targets, such as Axin2, Fgf8 and Wnt3a, is down regulated in Brachyury mutant embryos and we demonstrate that they are also Brachyury targets in the human. Surprisingly, we do not observe enrichment of the canonical T-domain DNA binding sequence 5′-TCACACCT-3′ in the vicinity of most Brachyury target genes. Rather, we have identified an (AC)n repeat sequence, which is conserved in the rat but not in human, zebrafish or Xenopus. We do not understand the significance of this sequence, but speculate that it enhances transcription factor binding in the regulatory regions of Brachyury target genes in rodents. Our work identifies the genomic targets of a key regulator of mesoderm formation in the early mouse embryo, thereby providing insights into the Brachyury-driven genetic regulatory network and allowing us to compare the function of Brachyury in different species.
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DOI：
10.1126/science.1162327
发表时间：
2009-06-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Badis G;Berger MF;Philippakis AA;Talukder S;Gehrke AR;Jaeger SA;Chan ET;Metzler G;Vedenko A;Chen X;Kuznetsov H;Wang CF;Coburn D;Newburger DE;Morris Q;Hughes TR;Bulyk ML
通讯作者：
Bulyk ML
影响因子：
9.8
作者：
Evans, Amanda Lisabeth;Bryant, James;Charnock-Jones, D. Stephen
通讯作者：
Charnock-Jones, D. Stephen
影响因子：
2.6
作者：
Clements, D;Taylor, HC;Stott, D
通讯作者：
Stott, D
影响因子：
2.6
作者：
ARMSTRONG, JF;PRITCHARDJONES, K;BARD, JBL
通讯作者：
BARD, JBL
影响因子：
2.6
作者：
Anderson, R;Copeland, TK;Wylie, C
通讯作者：
Wylie, C