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Translating dosage compensation to trisomy 21

机译：将剂量补偿转换为21三体

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摘要

Down's syndrome is a common disorder with enormous medical and social costs, caused by trisomy for chromosome 21. We tested the concept that gene imbalance across an extra chromosome can be de facto corrected by manipulating a single gene, XIST (the X-inactivation gene). Using genome editing with zinc finger nucleases, we inserted a large, inducible XIST transgene into the DYRKIA locus on chromosome 21, in Down's syndrome pluripotent stem cells. The XIST non-coding RNA coats chromosome 21 and triggers stable heterochromatin modifications, chromosome-wide transcriptional silencing and DNA methylation to form a 'chromosome 21 Barr body'. This provides a model to study human chromosome inactivation and creates a system to investigate genomic expression changes and cellular pathologies of trisomy 21, free from genetic and epigenetic noise. Notably, deficits in proliferation and neural rosette formation are rapidly reversed upon silencing one chromosome 21. Successful trisomy silencing in vitro also surmounts the major first step towards potential development of'chromosome therapy'.%在雌性哺乳动物中，被称为XIST的大非编码rnRNA触发两个X-染色体中其中一个上的基因转rn录被沉默。X-染色体的这种失活是重要的，因rn为双倍剂量的X基因将是有害的。在这项研究rn中，Jear]ne Lawrence及同事用“锌指核酸酶”rn来将一个可诱导的XIST转基因定位到来自“唐rn氏综合症”多能干细胞的21号染色体中(这种rn病是由第三个21号染色体的存在造成的)。他rn们发现，XIST RNA覆盖一个版本的21号染色rn体，并触发基因沉默，这说明了该方法对于研rn究“唐氏综合症”等染色体疾病以及研究基因rn疗法的潜力。
机译：唐氏综合症是由21号染色体的三体性疾病引起的，具有巨大的医疗和社会成本的常见疾病。我们测试了以下概念：可以通过操纵单个基因XIST（X灭活基因）来纠正额外染色体上的基因失衡。 。使用锌指核酸酶进行基因组编辑，我们在唐氏综合症多能干细胞的21号染色体上的DYRKIA基因座中插入了一个大的可诱导XIST转基因。 XIST非编码RNA覆盖21号染色体，并触发稳定的异染色质修饰，全染色体转录沉默和DNA甲基化，形成“ 21号巴尔巴尔体”。这提供了一个研究人类染色体失活的模型，并创建了一个系统来研究21号三体症的基因组表达变化和细胞病理，而没有遗传和表观遗传学噪声。值得注意的是，在沉默一条21号染色体后，增殖和神经玫瑰花结的形成缺陷会迅速逆转。在体外，成功的三体沉默也超越了“染色体疗法”潜在发展的主要第一步。 X-染色体的这种失活是重要的，因rn为双倍剂量的X基因将是有害的。在这项研究rn中，Jear] ne Lawrence及同事用“锌指核酸酶” rn来将一个可诱导的XIST转基因定位到来自“唐rn氏综合症”多能干细胞的21号染色体中（这种rn病是由第三个21号染色体的存在造成的）。他rn们发现，XIST RNA覆盖一个版本的21号染色rn体，并触发基因沉默，这说明了该方法对于研rn究“唐氏综合症” ”等染色体疾病以及研究基因rn疗法的潜力。

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  • 来源
    《Nature》 |2013年第7462期|296-300qt3|共6页
  • 作者

    Jun Jiang; Yuanchun Jing; Gregory J. Cost; Jen-Chieh Chiang; Heather J. Kolpa; Allison M. Cotton; Dawn M. Carone; Benjamin R. Carone; David A. Shivak; Dmitry Y. Guschin; Jocelynn R. Pearl; Edward J. Rebar; Meg Byron; Philip D. Gregory; Carolyn J. Brown; Fyodor D. Urnov; Lisa L. Hall; Jeanne B. Lawrence;

  • 作者单位

    Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA;

    Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA;

    Sangamo BioSciences, 501 Canal Boulevard,Richmond, California 94804, USA.;

    Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA;

    Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA;

    Department of Medical Genetics, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada;

    Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA;

    Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA;

    Sangamo BioSciences, 501 Canal Boulevard,Richmond, California 94804, USA.;

    Sangamo BioSciences, 501 Canal Boulevard,Richmond, California 94804, USA.;

    Sangamo BioSciences, 501 Canal Boulevard,Richmond, California 94804, USA.;

    Sangamo BioSciences, 501 Canal Boulevard,Richmond, California 94804, USA.;

    Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA;

    Sangamo BioSciences, 501 Canal Boulevard,Richmond, California 94804, USA.;

    Department of Medical Genetics, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada;

    Sangamo BioSciences, 501 Canal Boulevard,Richmond, California 94804, USA.;

    Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA;

    Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA;

  • 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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