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NANOG alone induces germ cells in primed epiblast in vitro by activation of enhancers

机译：单独的NANOG通过激活增强子在体外诱导初生上皮细胞中的生殖细胞

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Nanog, a core pluripotency factor in the inner cell mass of blastocysts, is also expressed in unipotent primordial germ cells (PGCs) in mice(1), where its precise role is yet unclear(2-4). We investigated this in an in vitro model, in which naive pluripotent embryonic stem (ES) cells cultured in basic fibroblast growth factor (bFGF) and activin A develop as epiblast-like cells (EpiLCs) and gain competence for a PGC-like fate(5). Consequently, bone morphogenetic protein 4 (BMP4), or ectopic expression of key germline transcription factors Prdm1, Prdm14 and Tfap2c, directly induce PGC-like cells (PGCLCs) in EpiLCs, but not in ES cells(6-8). Here we report an unexpected discovery that Nanog alone can induce PGCLCs in EpiLCs, independently of BMP4. We propose that after the dissolution of the naive ES-cell pluripotency network during establishment of EpiLCs(9,10), the epigenome is reset for cell fate determination. Indeed, we found genome-wide changes in NANOG-binding patterns between ES cells and EpiLCs, indicating epigenetic resetting of regulatory elements. Accordingly, we show that NANOG can bind and activate enhancers of Prdm1 and Prdm14 in EpiLCs in vitro; BLIMP1 (encoded by Prdm1) then directly induces Tfap2c. Furthermore, while SOX2 and NANOG promote the pluripotent state in ES cells, they show contrasting roles in EpiLCs, as Sox2 specifically represses PGCLC induction by Nanog. This study demonstrates a broadly applicable mechanistic principle for how cells acquire competence for cell fate determination, resulting in the context-dependent roles of key transcription factors during development.
机译：Nanog是胚泡内部细胞团中的核心多能性因子，它也在小鼠的单能原始生殖细胞（PGCs）中表达（1），其确切作用尚不清楚（2-4）。我们在体外模型中对此进行了研究，在该模型中，在碱性成纤维细胞生长因子（bFGF）和激活素A中培养的幼稚多能胚胎干（ES）细胞发展为上皮样细胞（EpiLCs），并获得了类似PGC的命运的能力（ 5）。因此，骨形态发生蛋白4（BMP4）或异种关键种系转录因子Prdm1，Prdm14和Tfap2c的异位表达在EpiLC中直接诱导了PGC样细胞（PGCLC），但在ES细胞中却没有诱导（6-8）。在这里，我们报告了一个意想不到的发现，即Nanog本身可以独立于BMP4诱导EpiLCs中的PGCLCs。我们建议在建立EpiLCs（9,10）期间将幼稚的ES细胞多能性网络解散后，将表观基因组重置以决定细胞命运。实际上，我们发现ES细胞和EpiLC之间的NANOG结合模式在全基因组范围内发生了变化，这表明调节元件的表观遗传复位。因此，我们显示NANOG可以结合和激活EpiLCs中的Prdm1和Prdd14的增强子。然后，BLIMP1（由Prdm1编码）直接诱导Tfap2c。此外，尽管SOX2和NANOG促进ES细胞的多能状态，但它们在EpiLC中显示出相反的作用，因为Sox2特异性抑制Nanog诱导的PGCLC诱导。这项研究证明了广泛适用的机制原理，说明细胞如何获得决定细胞命运的能力，从而导致发育过程中关键转录因子的背景依赖性作用。

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  • 来源
    《Nature》 |2016年第7586期|403-407|共5页
  • 作者

    Murakami Kazuhiro; Guenesdogan Ufuk; Zylicz Jan J.; Tang Walfred W. C.; Sengupta Roopsha; Kobayashi Toshihiro; Kim Shinseog; Butler Richard; Dietmann Sabine; Surani M. Azim;

  • 作者单位

    Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Cambridge CB2 1QN, England|Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3DY, England|Univ Cambridge, Wellcome Trust Med Res Council Stem Cell Inst, Cambridge CB2 1QR, England|RIKEN, Ctr Dev Biol, Lab Pluripotent Cell Studies, Chuo Ku, Kobe, Hyogo 6500047, Japan|Hokkaido Univ, Fac Adv Life Sci, Lab Mol & Cellular Biol, Kita Ku, Sapporo, Hokkaido 0010021, Japan;

    Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Cambridge CB2 1QN, England|Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3DY, England|Univ Cambridge, Wellcome Trust Med Res Council Stem Cell Inst, Cambridge CB2 1QR, England;

    Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Cambridge CB2 1QN, England|Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3DY, England|Univ Cambridge, Wellcome Trust Med Res Council Stem Cell Inst, Cambridge CB2 1QR, England;

    Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Cambridge CB2 1QN, England|Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3DY, England|Univ Cambridge, Wellcome Trust Med Res Council Stem Cell Inst, Cambridge CB2 1QR, England;

    Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Cambridge CB2 1QN, England|Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3DY, England|Univ Cambridge, Wellcome Trust Med Res Council Stem Cell Inst, Cambridge CB2 1QR, England;

    Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Cambridge CB2 1QN, England|Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3DY, England|Univ Cambridge, Wellcome Trust Med Res Council Stem Cell Inst, Cambridge CB2 1QR, England;

    Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Cambridge CB2 1QN, England|Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3DY, England|Univ Cambridge, Wellcome Trust Med Res Council Stem Cell Inst, Cambridge CB2 1QR, England;

    Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Cambridge CB2 1QN, England;

    Univ Cambridge, Wellcome Trust Med Res Council Stem Cell Inst, Cambridge CB2 1QR, England;

    Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Cambridge CB2 1QN, England|Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3DY, England|Univ Cambridge, Wellcome Trust Med Res Council Stem Cell Inst, Cambridge CB2 1QR, England;

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