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首页> 外文期刊>Nature >Genome editing reveals a role for OCT4 in human embryogenesis
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Genome editing reveals a role for OCT4 in human embryogenesis

机译：基因组编辑揭示了OCT4在人类胚胎发生中的作用

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摘要

Despite their fundamental biological and clinical importance, the molecular mechanisms that regulate the first cell fate decisions in the human embryo are not well understood. Here we use CRISPR-Cas9-mediated genome editing to investigate the function of the pluripotency transcription factor OCT4 during human embryogenesis. We identified an efficient OCT4-targeting guide RNA using an inducible human embryonic stem cell-based system and microinjection of mouse zygotes. Using these refined methods, we efficiently and specifically targeted the gene encoding OCT4 (POU5F1) in diploid human zygotes and found that blastocyst development was compromised. Transcriptomics analysis revealed that, in POU5F1-null cells, gene expression was downregulated not only for extra-embryonic trophectoderm genes, such as CDX2, but also for regulators of the pluripotent epiblast, including NANOG. By contrast, Pou5f1-null mouse embryos maintained the expression of orthologous genes, and blastocyst development was established, but maintenance was compromised. We conclude that CRISPR-Cas9-mediated genome editing is a powerful method for investigating gene function in the context of human development.
机译：尽管它们具有重要的生物学和临床意义，但调节人类胚胎中第一个细胞命运决定的分子机制仍未得到很好的理解。在这里，我们使用CRISPR-Cas9介导的基因组编辑来研究多能性转录因子OCT4在人类胚胎发生过程中的功能。我们使用诱导型基于人类胚胎干细胞的系统和小鼠合子的显微注射鉴定了一种靶向OCT4的有效引导RNA。使用这些改进的方法，我们有效和专门针对二倍体人受精卵中编码OCT4（POU5F1）的基因，发现胚泡发育受到损害。转录组学分析显示，在POU5F1无效细胞中，不仅胚外滋养外胚层基因（例如CDX2）的基因表达下调，而且多能上皮细胞（包括NANOG）的调节子也下调。相比之下，Pou5f1无效的小鼠胚胎保持了直系同源基因的表达，并建立了胚泡发育，但维持受到损害。我们得出的结论是，CRISPR-Cas9介导的基因组编辑是研究人类发育背景下基因功能的有力方法。

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  • 来源
    《Nature》 |2017年第7674期|67-73|共7页
  • 作者

    Fogarty Norah M. E.; McCarthy Afshan; Snijders Kirsten E.; Powell Benjamin E.; Kubikova Nada; Lakeley Paul B.; Lea Rebecca; Lder Kay E.; Wamaitha Sissy E.; Kim Daesik; Maciulyte Valdone; Kleinjung Jens; Kim Jin-Soo; Wells Dagan; Vallier Ludovic; Ertero Alessandro B.; Urner James M. A. T.; Niakan Kathy K.;

  • 作者单位

    Francis Crick Inst, Human Embryo & Stem Cell Lab, 1 Midland Rd, London NW1 1AT, England;

    Francis Crick Inst, Human Embryo & Stem Cell Lab, 1 Midland Rd, London NW1 1AT, England;

    Univ Cambridge, Dept Surg, HIPSC Core Facil, NIHR Cambridge Biomed Res Ctr, Cambridge Biomed Campus, Cambridge CB2 0SZ, England;

    Francis Crick Inst, Sex Chromosome Biol Lab, London NW1 1AT, England;

    Univ Oxford, John Radcliffe Hosp, Nuffield Dept Obstet & Gynaecol, Oxford OX3 9DU, England;

    Francis Crick Inst, Human Embryo & Stem Cell Lab, 1 Midland Rd, London NW1 1AT, England;

    Francis Crick Inst, Human Embryo & Stem Cell Lab, 1 Midland Rd, London NW1 1AT, England;

    Bourn Hall Clin, Cambridge CB23 2TN, England;

    Francis Crick Inst, Human Embryo & Stem Cell Lab, 1 Midland Rd, London NW1 1AT, England;

    Seoul Natl Univ, Dept Chem, Seoul 151747, South Korea;

    Francis Crick Inst, Sex Chromosome Biol Lab, London NW1 1AT, England;

    Francis Crick Inst, Bioinformat Facil, London NW1 1AT, England;

    Seoul Natl Univ, Dept Chem, Seoul 151747, South Korea|Inst for Basic Sci Korea, Ctr Genome Engn, Daejeon 34047, South Korea;

    Univ Oxford, John Radcliffe Hosp, Nuffield Dept Obstet & Gynaecol, Oxford OX3 9DU, England;

    Univ Cambridge, Dept Surg, HIPSC Core Facil, NIHR Cambridge Biomed Res Ctr, Cambridge Biomed Campus, Cambridge CB2 0SZ, England|Wellcome Trust Sanger Inst, Wellcome Genome Campus, Cambridge CB10 1SA, England|Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0SZ, England|Univ Cambridge, Dept Surg, Anne McLaren Lab, Biomed Res Ctr, Cambridge CB2 0SZ, England;

    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0SZ, England|Univ Cambridge, Dept Surg, Anne McLaren Lab, Biomed Res Ctr, Cambridge CB2 0SZ, England|Univ Washington, Dept Pathol, Seattle, WA 98109 USA;

    Francis Crick Inst, Sex Chromosome Biol Lab, London NW1 1AT, England;

    Francis Crick Inst, Human Embryo & Stem Cell Lab, 1 Midland Rd, London NW1 1AT, England;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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