Format

Send to

Choose Destination
Front Genet. 2018 Aug 15;9:319. doi: 10.3389/fgene.2018.00319. eCollection 2018.

A Cosine Similarity-Based Method to Infer Variability of Chromatin Accessibility at the Single-Cell Level.

Cai S1,2,3, Georgakilas GK1,2,3, Johnson JL1,2,3, Vahedi G1,2,3.

Author information

1
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
2
Penn Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
3
Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.

Abstract

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.

KEYWORDS:

ATAC-seq; chromatin; code:R; multidimensional scaling; single-cell; variation

Supplemental Content

Full text links

Icon for Frontiers Media SA Icon for PubMed Central
Loading ...
Support Center