Single-cell chromatin accessibility reveals principles of regulatory variation.
Single-cell chromatin accessibility reveals principles of regulatory variation.
复制标题
单细胞染色质可及性揭示了调节变化的原理。
DOI：
10.1038/nature14590
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发表时间：
2015-07-23
期刊：
影响因子：
64.8
通讯作者：
Greenleaf WJ
中科院分区：
文献类型：
--
作者：
Buenrostro JD;Wu B;Litzenburger UM;Ruff D;Gonzales ML;Snyder MP;Chang HY;Greenleaf WJ
细胞间变异是生命的普遍特征，影响着从发育可塑性到肿瘤异质性等广泛的生物学现象。虽然最近的进展已经提高了我们记录细胞表型变异的能力，但从相同的DNA序列产生变异的基本机制仍然难以捉摸。在这里，我们揭示了景观和细胞DNA调控变异的原则，通过开发一个强大的方法来映射可访问的基因组的个别细胞通过测定转座酶可访问的染色质使用测序（ATAC-seq）。来自数百个单细胞的单细胞ATAC-seq（scATAC-seq）图谱与来自数千万个细胞的可及性图谱非常相似，并提供了对细胞间变异的深入了解。可及性方差系统地与特定的反式因子和顺式元件，我们发现的反式因子的组合与诱导或抑制细胞到细胞的变异性。我们进一步确定了跨8种细胞类型与细胞类型特异性可及性差异相关的反式因子集。细胞周期或转录因子信号传导的靶向扰动引起这种观察到的变异性的刺激特异性变化。整个基因组顺式可及性变异的模式从头概括了染色体拓扑结构域，将单细胞可及性变异与三维基因组组织联系起来。总之，DNA可及性的单细胞分析为“调节组”的细胞变异提供了新的见解。
Cell-to-cell variation is a universal feature of life that impacts a wide range of biological phenomena, from developmental plasticity to tumor heterogeneity. While recent advances have improved our ability to document cellular phenotypic variation the fundamental mechanisms that generate variability from identical DNA sequences remain elusive. Here we reveal the landscape and principles of cellular DNA regulatory variation by developing a robust method for mapping the accessible genome of individual cells via assay for transposase-accessible chromatin using sequencing (ATAC-seq). Single-cell ATAC-seq (scATAC-seq) maps from hundreds of single-cells in aggregate closely resemble accessibility profiles from tens of millions of cells and provides insights into cell-to-cell variation. Accessibility variance is systematically associated with specific trans-factors and cis-elements, and we discover combinations of trans-factors associated with either induction or suppression of cell-to-cell variability. We further identify sets of trans-factors associated with cell-type specific accessibility variance across 8 cell types. Targeted perturbations of cell cycle or transcription factor signaling evoke stimulus-specific changes in this observed variability. The pattern of accessibility variation in cis across the genome recapitulates chromosome topological domains de novo, linking single-cell accessibility variation to three-dimensional genome organization. All together, single-cell analysis of DNA accessibility provides new insight into cellular variation of the “regulome.”