A Cosine Similarity-Based Method to Infer Variability of Chromatin Accessibility at the Single-Cell Level.
A Cosine Similarity-Based Method to Infer Variability of Chromatin Accessibility at the Single-Cell Level.
复制标题
DOI：
10.3389/fgene.2018.00319
复制
发表时间：
2018
影响因子：
3.7
通讯作者：
Vahedi G
中科院分区：
文献类型：
--
作者：
Cai S;Georgakilas GK;Johnson JL;Vahedi G
发育中的几代细胞之间的细胞同一性通过表观基因组传播，特别是通过染色质的可及部分。现在可以使用转座酶可及染色质的单细胞测定法(scATAC-seq)在单细胞分辨率下测量染色质的可及性，这可以揭示表型变异背后的调控变异。然而，单细胞染色质可及性数据是稀疏的、二进制的和高维的，这导致了独特的计算挑战。为了克服这些困难，我们开发了PRISM，这是一种计算工作流程，可以量化细胞到细胞染色质的可及性差异，同时控制技术偏差。棱镜是一种新的基于多维尺度的方法，它使用角度余弦距离度量与距离空间质心的距离相结合。PRISM考虑了单个细胞在每个基因组区域的可及性差异。使用我们实验室生成并公开获得的数据，我们表明PRISM的性能优于现有的算法，后者依赖于一组基因组区域的信号聚合。在测量染色质可及性方面，棱镜在低覆盖率的细胞中表现出对噪声的稳健性。我们的方法揭示了以前未检测到的可访问性差异，其中可访问站点在小区之间不同，但可访问站点的总数是恒定的。我们还表明，PRISM，但不是现有的算法，可以发现CTCF结合位点可访问性的抑制异质性。我们最新的方法揭示了新的生物学结果，对染色质结构的细胞异质性具有深远的影响。
Cellular identity between generations of developing cells is propagated through the epigenome particularly via the accessible parts of the chromatin. It is now possible to measure chromatin accessibility at single-cell resolution using single-cell assay for transposase accessible chromatin (scATAC-seq), which can reveal the regulatory variation behind the phenotypic variation. However, single-cell chromatin accessibility data are sparse, binary, and high dimensional, leading to unique computational challenges. To overcome these difficulties, we developed PRISM, a computational workflow that quantifies cell-to-cell chromatin accessibility variation while controlling for technical biases. PRISM is a novel multidimensional scaling-based method using angular cosine distance metrics coupled with distance from the spatial centroid. PRISM takes differences in accessibility at each genomic region between single cells into account. Using data generated in our lab and publicly available, we showed that PRISM outperforms an existing algorithm, which relies on the aggregate of signal across a set of genomic regions. PRISM showed robustness to noise in cells with low coverage for measuring chromatin accessibility. Our approach revealed the previously undetected accessibility variation where accessible sites differ between cells but the total number of accessible sites is constant. We also showed that PRISM, but not an existing algorithm, can find suppressed heterogeneity of accessibility at CTCF binding sites. Our updated approach uncovers new biological results with profound implications on the cellular heterogeneity of chromatin architecture.
登录
查看更多内容
影响因子：
64.5
作者：
Schmidt D;Schwalie PC;Wilson MD;Ballester B;Gonçalves A;Kutter C;Brown GD;Marshall A;Flicek P;Odom DT
通讯作者：
Odom DT
影响因子：
32.4
作者：
Johnson JL;Georgakilas G;Petrovic J;Kurachi M;Cai S;Harly C;Pear WS;Bhandoola A;Wherry EJ;Vahedi G
通讯作者：
Vahedi G
影响因子：
30.8
作者：
Corces, M. Ryan;Buenrostro, Jason D.;Wu, Beijing;Greenside, Peyton G.;Chan, Steven M.;Koenig, Julie L.;Snyder, Michael P.;Pritchard, Jonathan K.;Kundaje, Anshul;Gkeenleaf, William J.;Majeti, Ravindra;Chang, Howard Y.
通讯作者：
Chang, Howard Y.
单细胞染色质可及性揭示了调节变化的原理。
影响因子：
64.8
作者：
Buenrostro JD;Wu B;Litzenburger UM;Ruff D;Gonzales ML;Snyder MP;Chang HY;Greenleaf WJ
通讯作者：
Greenleaf WJ
影响因子：
64.8
作者：
Tanay A;Regev A
通讯作者：
Regev A