Cell-free DNA Comprises an In Vivo Nucleosome Footprint that Informs Its Tissues-Of-Origin.
Cell-free DNA Comprises an In Vivo Nucleosome Footprint that Informs Its Tissues-Of-Origin.
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DOI：
10.1016/j.cell.2015.11.050
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发表时间：
2016-01-14
期刊：
影响因子：
64.5
通讯作者：
Shendure J
中科院分区：
文献类型：
--
作者：
Snyder MW;Kircher M;Hill AJ;Daza RM;Shendure J
核小体定位在不同细胞类型之间存在差异。通过对从循环血浆中分离出的无细胞DNA（cfDNA）进行深度测序，我们绘制了全基因组体内核小体占据情况的图谱，并发现短的cfDNA片段带有转录因子的足迹。cfDNA核小体占据情况与在细胞中观察到的核结构、基因结构和表达密切相关，这表明它们可以指示来源细胞类型。从健康个体的cfDNA推断出的核小体间距与淋巴细胞和髓细胞的表观遗传特征相关性最强，这与造血细胞死亡是cfDNA的正常来源一致。我们基于这一观察结果展示了如何利用核小体足迹来推断在癌症等病理状态下对cfDNA有贡献的细胞类型。由于这一策略不依赖于cfDNA和细胞DNA基因型的差异，它可能使我们能够对比目前更广泛的临床状况进行无创监测。
Nucleosome positioning varies between cell types. By deep sequencing cell-free DNA (cfDNA) isolated from circulating blood plasma, we generated maps of genome-wide in vivo nucleosome occupancy, and found that short cfDNA fragments harbor footprints of transcription factors. The cfDNA nucleosome occupancies correlate well with the nuclear architecture, gene structure and expression observed in cells, suggesting that they could indicate the cell-type of origin. Nucleosome spacing inferred from cfDNA in healthy individuals correlates most strongly with epigenetic features of lymphoid and myeloid cells, consistent with hematopoietic cell death as the normal source of cfDNA. We build on this observation to show how nucleosome footprints can be used to infer cell types contributing to cfDNA in pathological states such as cancer. Since this strategy does not rely on differing cfDNA and cellular DNA genotypes, it may enable the noninvasive monitoring of a much broader set of clinical conditions than currently possible.