Genome-wide Kinase-Chromatin Interactions Reveal the Regulatory Network of ERK Signaling in Human Embryonic Stem Cells
Genome-wide Kinase-Chromatin Interactions Reveal the Regulatory Network of ERK Signaling in Human Embryonic Stem Cells
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DOI：
10.1016/j.molcel.2013.04.030
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发表时间：
2013-06-27
期刊：
影响因子：
16
通讯作者：
Ng, Huck-Hui
中科院分区：
文献类型：
--
作者：
Goeke, Jonathan;Chan, Yun-Shen;Ng, Huck-Hui
细胞外信号调节激酶（ERK）/丝裂原激活蛋白激酶信号转导级联是调节发育和疾病中增殖和分化的关键途径之一。 ERK 信号传导是人类胚胎干细胞 (hESC) 自我更新特性所必需的。在这里，我们通过绘制 hESC 中 ERK2 的全基因组激酶-染色质相互作用来研究 ERK 信号级联在 DNA 上的收敛。我们观察到 ERK2 结合发生在非编码基因和组蛋白、细胞周期、代谢和多能性相关基因附近。我们发现转录因子 ELK1 在 hESC 中至关重要，并且 ERK2 共同占据与 ELK1 结合的启动子。引人注目的是，在没有 ERK2 的情况下，由 ELK1 结合的启动子被 Polycomb 组蛋白占据，这些蛋白抑制参与谱系定型的基因。总之，我们提出了一种模型，其中细胞外信号刺激的增殖和内在的分化抑制相结合以维持 hESC 的身份。
The extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase signal-transduction cascade is one of the key pathways regulating proliferation and differentiation in development and disease. ERK signaling is required for human embryonic stem cells' (hESCs') self-renewing property. Here, we studied the convergence of the ERK signaling cascade at the DNA by mapping genome-wide kinase-chromatin interactions for ERK2 in hESCs. We observed that ERK2 binding occurs near noncoding genes and histone, cell-cycle, metabolism, and pluripotency-associated genes. We find that the transcription factor ELK1 is essential in hESCs and that ERK2 co-occupies promoters bound by ELK1. Strikingly, promoters bound by ELK1 without ERK2 are occupied by Polycomb group proteins that repress genes involved in lineage commitment. In summary, we propose a model wherein extracellular-signaling-stimulated proliferation and intrinsic repression of differentiation are integrated to maintain the identity of hESCs.