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Genome-wide characterization of the routes to pluripotency

机译:全基因组途径的多能性表征

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摘要

Somatic cell reprogramming to a pluripotent state continues to challenge many of our assumptions about cellular specification, and despite major efforts, we lack a complete molecular characterization of the reprograming process. To address this gap in knowledge, we generated extensive transcriptomic, epigenomic and proteomic data sets describing the reprogramming routes leading from mouse embryonic fibroblasts to induced pluripotency. Through integrative analysis, we reveal that cells transition through distinct gene expression and epigenetic signatures and bifurcate towards reprogramming transgene-dependent and -independent stable pluripotent states. Early transcriptional events, driven by high levels of reprogramming transcription factor expression, are associated with widespread loss of histone H3 lysine 27 (H3K27me3) trimethylation, representing a general opening of the chromatin state. Maintenance of high trans-gene levels leads to re-acquisition of H3K27me3 and a stable pluripotent state that is alternative to the embryonic stem cell (ESC) -like fate. Lowering transgene levels at an intermediate phase, however, guides the process to the acquisition of ESC-like chromatin and DNA methylation signature.%"Project Grandiose"联合项目组的研究人员,在本期Nature上发表的两篇论文中和在Nature Communications上同时发表的三篇论文中,报告了他们为表征与由转录因子介导的向多能性的重新编程有关的蛋白、DNA和RNA变化所做工作。在第一篇Nature论文中,Andras Nagy及同事报告说,当要让小鼠胚胎成纤维细胞表达高水平的重新编程因子时,它们会达到另一种状态,即多能稳定状态,该状态被称为F-class(这里的“F”是英文'Fuzzy'的第一个字母,原因是细胞群在培养中外观是“模糊”的)。第二篇论文对描述实现多能性的途径的转录组、表观基因组和蛋白质组数据集进行了广泛分析。它们描述了实现诱导多能性的几个路径的存在,这些路径以截然不同的表观遗传事件为特征。在一篇News & Views文章中,Juan Carlos Izpisua Belmonte在其他最新研究工作的背景下对所有五篇论文的结果进行了讨论,并对多能性的另类状态之存在的可能性进行了推测。
机译:将体细胞重编程为多能状态继续挑战着许多有关细胞规格的假设,尽管付出了巨大的努力,我们仍缺乏对重编程过程进行完整的分子表征。为了解决这一知识差距,我们生成了广泛的转录组学,表观基因组学和蛋白质组学数据集,描述了从小鼠胚胎成纤维细胞到诱导多能性的重编程途径。通过整合分析,我们揭示了细胞通过独特的基因表达和表观遗传学特征过渡,并分叉向重新编程转基因依赖性和非依赖性稳定多能态。由高水平的重编程转录因子表达驱动的早期转录事件与组蛋白H3赖氨酸27(H3K27me3)三甲基化的广泛丧失有关,代表染色质状态的普遍开放。维持高转基因水平导致H3K27me3的重新获得和稳定的多能状态,该状态可替代胚胎干细胞(ESC)样的命运。然而,在中间阶段降低转基因水平,将其引导至类ESC染色质和DNA甲基化标记的获得过程。%“宏伟计划”联合项目组的研究人员,在本期自然上发表的两篇论文中和在自然通讯上同时发表的三篇论文中,报告了他们为表征与由转录因子介导的向多能性的重新编程有关的蛋白,DNA和RNA变化处理工作。在第一篇自然论文中,Andras Nagy及同事报告说,当要让小鼠插入成纤维细胞表达高水平的重新编程因子时,它们会达到另一种状态,即多能稳定状态,该状态被称为F-class(这里的“ F”是英文“ Fuzzy”的第一个字母,原因是细胞群在培养中外观是“模糊”的)。第二篇论文对描述实现多能性的传递的转录组,表观基因组和蛋白质组数据集进行了广泛的分析。它们描述了实现诱导多能性的几个路径的存在,这些路径以截然不同的表观遗传事件为特征。在新闻与观点文章中,Juan Carlos Izpisua Belmonte在其他最新研究工作的背景下对所有五篇论文的结果进行了讨论,转变多能性的另类状态之存在的可能进行了推测。

著录项

  • 来源
    《Nature》 |2014年第7530期|198-206a2|共10页
  • 作者单位

    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada;

    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada,Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5T 3H7, Canada;

    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada;

    Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands,Netherlands Proteomics Centre, Padualaan 8, 3584CH Utrecht, The Netherlands;

    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada,Institute of Medical Science, University of Toronto, Toronto, Ontario M5T 3H7, Canada;

    Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Acton (Canberra), ACT 2601, Australia;

    Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland 4072, Australia;

    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada;

    Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 110-799, South Korea,Department of Biomedical Sciences and Biochemistry, Seoul National University College of Medicine, Seoul 110-799, South Korea;

    Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia,QIMR Berghofer Medical Research Institute, Genomic Biology Lab, 300 Herston Road, Herston, Queensland 4006, Australia;

    Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia;

    Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands,Netherlands Proteomics Centre, Padualaan 8, 3584CH Utrecht, The Netherlands,Proteomics Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain;

    Gene and Stem Cell Therapy Program and Bioinformatics Lab, Centenary Institute, Camperdown 2050, NSW, Australia & Sydney Medical School, 31 University of Sydney 2006, New South Wales, Australia;

    Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland 4072, Australia;

    Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Acton (Canberra), ACT 2601, Australia,Genome Discovery Unit, The John Curtin School of Medical Research, The Australian National University, Acton (Canberra) 2601, ACT, Australia;

    Institute of Biomaterials and Biomedical Engineering (IBBME), University of Toronto, Toronto M5S-3G9, Canada,The Donnelly Centre for Cellular and Biomolecular Research (CCBR), University of Toronto, Toronto M5S 3E1, Canada;

    Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 110-799, South Korea,Life Science Institute, Macrogen Inc., Seoul 153-781, South Korea;

    Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia;

    Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia,The University of Queensland Diamantina Institute, Translational Research Institute, 37 Kent Street, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia;

    Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 110-799, South Korea,Department of Biomedical Sciences and Biochemistry, Seoul National University College of Medicine, Seoul 110-799, South Korea;

    Department of Systems & Computational Biology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA;

    Institute of Biomaterials and Biomedical Engineering (IBBME), University of Toronto, Toronto M5S-3G9, Canada;

    Gene and Stem Cell Therapy Program and Bioinformatics Lab, Centenary Institute, Camperdown 2050, NSW, Australia & Sydney Medical School, 31 University of Sydney 2006, New South Wales, Australia;

    Gene and Stem Cell Therapy Program and Bioinformatics Lab, Centenary Institute, Camperdown 2050, NSW, Australia & Sydney Medical School, 31 University of Sydney 2006, New South Wales, Australia,Cell and Molecular Therapies, Royal Prince Alfred Hospital, Camperdown 2050, New South Wales, Australia;

    Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia;

    Institute of Biomaterials and Biomedical Engineering (IBBME), University of Toronto, Toronto M5S-3G9, Canada,The Donnelly Centre for Cellular and Biomolecular Research (CCBR), University of Toronto, Toronto M5S 3E1, Canada;

    Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland 4072, Australia,College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK;

    Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Acton (Canberra), ACT 2601, Australia,Victor Chang Cardiac Research Institute, Darlinghurst (Sydney), New South Wales 2010, Australia;

    Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 110-799, South Korea,Department of Biomedical Sciences and Biochemistry, Seoul National University College of Medicine, Seoul 110-799, South Korea,Life Science Institute, Macrogen Inc., Seoul 153-781, South Korea;

    Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands,Netherlands Proteomics Centre, Padualaan 8, 3584CH Utrecht, The Netherlands;

    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada,Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada,Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario M5S 1E2, Canada;

    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada,Institute of Medical Science, University of Toronto, Toronto, Ontario M5T 3H7, Canada,Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario M5S 1E2, Canada;

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