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Genome-wide detection of DNase I hypersensitive sites in single cells and FFPE tissue samples

机译：全基因组检测单细胞和FFPE组织样品中DNase I超敏位点

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摘要

DNase I hypersensitive sites (DHSs) provide important information on the presence of transcriptional regulatory elements and the state of chromatin in mammalian cells(1-3). Conventional DNase sequencing (DNase-seq) for genome-wide DHSs profiling is limited by the requirement of millions of cells(4,5). Here we report an ultrasensitive strategy, called single-cell DNase sequencing (scDNase-seq) for detection of genome-wide DHSs in single cells. We show that DHS patterns at the single-cell level are highly reproducible among individual cells. Among different single cells, highly expressed gene promoters and enhancers associated with multiple active histone modifications display constitutive DHS whereas chromatin regions with fewer histone modifications exhibit high variation of DHS. Furthermore, the single-cell DHSs predict enhancers that regulate cell-specific gene expression programs and the cell-to-cell variations of DHS are predictive of gene expression. Finally, we apply scDNase-seq to pools of tumour cells and pools of normal cells, dissected from formalin-fixed paraffin-embedded tissue slides from patients with thyroid cancer, and detect thousands of tumour-specific DHSs. Many of these DHSs are associated with promoters and enhancers critically involved in cancer development. Analysis of the DHS sequences uncovers one mutation (chr18: 52417839G> C) in the tumour cells of a patient with follicular thyroid carcinoma, which affects the binding of the tumour suppressor protein p53 and correlates with decreased expression of its target gene TXNL1. In conclusion, scDNase-seq can reliably detect DHSs in single cells, greatly extending the range of applications of DHS analysis both for basic and for translational research, and may provide critical information for personalized medicine.
机译：DNase I高敏位点（DHS）提供有关哺乳动物细胞中转录调控元件的存在和染色质状态的重要信息（1-3）。数百万个细胞的需求限制了用于全基因组DHS谱图的常规DNase测序（DNase-seq）（4,5）。在这里，我们报告了一种称为单细胞DNase测序（scDNase-seq）的超灵敏策略，用于检测单细胞中的全基因组DHS。我们表明，单细胞水平的DHS模式在单个细胞之间是高度可复制的。在不同的单细胞中，与多种活性组蛋白修饰相关的高表达基因启动子和增强子显示组成型DHS，而组蛋白修饰较少的染色质区域则表现出DHS的高度变异。此外，单细胞DHS可以预测调节细胞特异性基因表达程序的增强子，而DHS的细胞间变异可预测基因表达。最后，我们将scDNase-seq应用于从甲状腺癌患者的福尔马林固定石蜡包埋的组织玻片中解剖出来的肿瘤细胞库和正常细胞库中，并检测数千种肿瘤特异性DHS。这些DHS中的许多都与关键参与癌症发展的启动子和增强子有关。对DHS序列的分析发现，在滤泡性甲状腺癌患者的肿瘤细胞中发现了一个突变（chr18：52417839G> C），该突变影响肿瘤抑制蛋白p53的结合并与其靶基因TXNL1的表达降低相关。总之，scDNase-seq可以可靠地检测单个细胞中的DHS，从而大大扩展了DHS分析在基础研究和转化研究中的应用范围，并可能为个性化医学提供关键信息。

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  • 来源
    《Nature》 |2015年第7580期|142-146|共5页
  • 作者

    Jin Wenfei; Tang Qingsong; Wan Mimi; Cui Kairong; Zhang Yi; Ren Gang; Ni Bing; Sklar Jeffrey; Przytycka Teresa M.; Childs Richard; Levens David; Zhao Keji;

  • 作者单位

    NHLBI, Syst Biol Ctr, Div Intramural Res, NIH, Bethesda, MD 20892 USA;

    NHLBI, Syst Biol Ctr, Div Intramural Res, NIH, Bethesda, MD 20892 USA;

    Yale Univ, Dept Pathol, Sch Med, New Haven, CT 06520 USA;

    NHLBI, Syst Biol Ctr, Div Intramural Res, NIH, Bethesda, MD 20892 USA;

    NHLBI, Syst Biol Ctr, Div Intramural Res, NIH, Bethesda, MD 20892 USA|Peoples Liberat Army, Mil Med Univ 3, Inst Immunol, Chongqing 400038, Peoples R China;

    NHLBI, Syst Biol Ctr, Div Intramural Res, NIH, Bethesda, MD 20892 USA|Northwest A&F Univ, Coll Anim Sci & Technol, Yangling 712100, Shaanxi, Peoples R China;

    Peoples Liberat Army, Mil Med Univ 3, Inst Immunol, Chongqing 400038, Peoples R China;

    Yale Univ, Dept Pathol, Sch Med, New Haven, CT 06520 USA;

    Natl Lib Med, Computat Biol Branch, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20892 USA;

    NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA;

    NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA;

    NHLBI, Syst Biol Ctr, Div Intramural Res, NIH, Bethesda, MD 20892 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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