RUNX1 reshapes the epigenetic landscape at the onset of haematopoiesis.
RUNX1 reshapes the epigenetic landscape at the onset of haematopoiesis.
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DOI：
10.1038/emboj.2012.275
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发表时间：
2012-11-14
期刊：
影响因子：
11.4
通讯作者：
Bonifer, Constanze
中科院分区：
文献类型：
--
作者：
Lichtinger, Monika;Ingram, Richard;Hannah, Rebecca;Mueller, Dorothee;Clarke, Deborah;Assi, Salam A.;Lie-A-Ling, Michael;Noailles, Laura;Vijayabaskar, M. S.;Wu, Mengchu;Tenen, Daniel G.;Westhead, David R.;Kouskoff, Valerie;Lacaud, Georges;Goettgens, Berthold;Bonifer, Constanze
关键词：
造血过程中的细胞命运决定由谱系特异性转录因子，如RUNX 1，SCL/TAL 1，FLI 1和C/EBP家族成员控制。为了深入了解这些转录因子在胚胎发育过程中如何调节造血基因的激活，我们测量了从造血内皮细胞（HE）到造血祖细胞的RUNX 1依赖性转变过程中转录因子组装在其靶基因上的全基因组动态。使用表达可诱导Runx 1基因的Runx 1 −/−胚胎干细胞分化模型，我们表明在缺乏RUNX 1的情况下，造血基因结合SCL/TAL 1，FLI 1和C/EBPβ，并且这种早期引发是骨髓主调节因子PU.1及其下游靶点正确表达所必需的。诱导后，RUNX 1与许多从头位点结合，引发组蛋白乙酰化的局部增加和SCL/TAL 1和FLI 1结合模式的快速全局改变。因此，获得由Runx 1控制的造血命运并不代表在预先存在的HE程序之上建立新的调控层，而是需要对谱系特异性转录因子组装进行全局重组。
Cell fate decisions during haematopoiesis are governed by lineage-specific transcription factors, such as RUNX1, SCL/TAL1, FLI1 and C/EBP family members. To gain insight into how these transcription factors regulate the activation of haematopoietic genes during embryonic development, we measured the genome-wide dynamics of transcription factor assembly on their target genes during the RUNX1-dependent transition from haemogenic endothelium (HE) to haematopoietic progenitors. Using a Runx1−/− embryonic stem cell differentiation model expressing an inducible Runx1 gene, we show that in the absence of RUNX1, haematopoietic genes bind SCL/TAL1, FLI1 and C/EBPβ and that this early priming is required for correct temporal expression of the myeloid master regulator PU.1 and its downstream targets. After induction, RUNX1 binds to numerous de novo sites, initiating a local increase in histone acetylation and rapid global alterations in the binding patterns of SCL/TAL1 and FLI1. The acquisition of haematopoietic fate controlled by Runx1 therefore does not represent the establishment of a new regulatory layer on top of a pre-existing HE program but instead entails global reorganization of lineage-specific transcription factor assemblies.
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