Induction of a Human Pluripotent State with Distinct Regulatory Circuitry that Resembles Preimplantation Epiblast
Induction of a Human Pluripotent State with Distinct Regulatory Circuitry that Resembles Preimplantation Epiblast
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DOI：
10.1016/j.stem.2013.11.015
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发表时间：
2013-12-05
期刊：
影响因子：
23.9
通讯作者：
Ng, Huck-Hui
中科院分区：
文献类型：
--
作者：
Chan, Yun-Shen;Goeke, Jonathan;Ng, Huck-Hui
人胚胎干细胞（human embryonic stem cells，hESC）来源于囊胚的内细胞团。尽管具有多能性的共同特性，但hESC与植入前胚泡的上胚层细胞明显不同。在这里，我们使用三种小分子抑制剂的组合来维持LIF信号传导依赖性hESC状态（3iL hESC）中的hESC，其中NANOG和外胚层富集基因（如KLF4、DPPA3和TBX3）的表达升高。全基因组转录组分析证实了3iL hESC的表达特征与天然植入前上胚层细胞具有相似性。我们还表明，3iL人胚胎干细胞有一个独特的表观遗传景观，其特征在于植入前外胚层基因的去抑制。使用NANOG和OCT 4的全基因组结合谱，我们确定了有助于调节电路重新布线的增强子。总之，我们的研究确定了一个独特的人胚胎干细胞状态与明确的调控电路，这将有助于未来的分析人类植入前胚胎发生和多能性。
Human embryonic stem cells (hESCs) are derived from the inner cell mass of the blastocyst. Despite sharing the common property of pluripotency, hESCs are notably distinct from epiblast cells of the preimplantation blastocyst. Here we use a combination of three small-molecule inhibitors to sustain hESCs in a LIF signaling-dependent hESC state (3iL hESCs) with elevated expression of NANOG and epiblast-enriched genes such as KLF4, DPPA3, and TBX3. Genome-wide transcriptome analysis confirms that the expression signature of 3iL hESCs shares similarities with native preimplantation epiblast cells. We also show that 3iL hESCs have a distinct epigenetic landscape, characterized by derepression of preimplantation epiblast genes. Using genome-wide binding profiles of NANOG and OCT4, we identify enhancers that contribute to rewiring of the regulatory circuitry. In summary, our study identifies a distinct hESC state with defined regulatory circuitry that will facilitate future analysis of human preimplantation embryogenesis and pluripotency.