Cicero Predicts cis-Regulatory DNA Interactions from Single-Cell Chromatin Accessibility Data

Pliner, Hannah A.; Packer, Jonathan S.; McFaline-Figueroa, José L.; Cusanovich, Darren A.; Daza, Riza M.; Aghamirzaie, Delasa; Srivatsan, Sanjay; Qiu, Xiaojie; Jackson, Dana L.; Minkina, Anna; Adey, Andrew; Steemers, Frank J.; Shendure, Jay; Trapnell, Cole

doi:10.1016/j.molcel.2018.06.044

Cited by 654 publications

(865 citation statements)

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“…We applied this analysis to our dataset, which enabled us to interconnect 98,947 of our 125,645 peaks (78.8%). We generated 149,010 correlations with coaccessbility scores ≥ 0.15, a threshold consistent with previous literature 2, 13,35 . Of these, 0.5% (706) were promoter-promoter links, 7.6% (11,289) distal-promoter links, and 92% (137,015) distal-distal links.…”

Section: Mainmentioning

confidence: 88%

“…Single-cell ATAC-seq data provides a unique opportunity to identify tightly coordinated coaccessible regulatory elements using a recentlydescribed strategy, cicero 35 . We applied this analysis to our dataset, which enabled us to interconnect 98,947 of our 125,645 peaks (78.8%).…”

Section: Mainmentioning

confidence: 99%

“…The use of nearby enhancer regions has an improved positive predictive value for transcription over promoter accessibility alone 35 . To leverage nearby accessibility peaks in this fashion, we employed the cicero package from the Trapnell group using default settings (v1.0.15) 35 . We generated cis-coaccessiblity networks using these coaccessbility scores (cut-off of coaccessibility scores ≥ 0.15; Fig.…”

Section: Competing Financial Interestsmentioning

confidence: 99%

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Improved single-cell ATAC-seq reveals chromatin dynamics of in vitro corticogenesis

Mulqueen

DeRosa

Thornton

et al. 2019

Preprint

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Development is a complex process that requires the precise modulation of regulatory gene networks controlled through dynamic changes in the epigenome. Single-cell -omic technologies provide an avenue for understanding the mechanisms of these processes by capturing the progression of epigenetic cell states during the course of cellular differentiation using in vitro or in vivo models 1 . However, current single-cell epigenomic methods are limited in the information garnered per individual cell, which in turn limits their ability to measure chromatin dynamics and state shifts. Single-cell combinatorial indexing (sci-) has been applied as a strategy for identifying single-cell -omic originating libraries and removes the necessity of single-cell, single-compartment chemistry 2 . Here, we report an improved sci-assay for transposase accessible chromatin by sequencing (ATAC-seq), which utilizes the small molecule inhibitor Pitstop 2™ (scip-ATAC-seq) 3 . We demonstrate that these improvements, which theoretically could be applied to any in situ transposition method for single-cell library preparation, significantly increase the ability of transposase to enter the nucleus and generate highly complex singlecell libraries, without altering biological signal. We applied sci-ATAC-seq and scip-ATAC-seq to characterize the chromatin dynamics of developing forebrain-like organoids, an in vitro model of human corticogenesis 4 . Using these data, we characterized novel putative regulatory elements, compared the epigenome of the organoid model to human cortex data, generated a high-resolution pseudotemporal map of chromatin accessibility through differentiation, and measured epigenomic changes coinciding with a neurogenic fate decision point. Finally, we combined transcription factor motif accessibility with gene activity (GA) scores to directly observe the dynamics of complex regulatory programs that regulate neurogenesis through developmental pseudotime. Overall, scip-ATAC-seq increases information content per cell and bolsters the potential for future single-cell studies into complex developmental processes. F.J.S. and R.R. are employees of Illumina Inc. Data and software availabilityA wrapper for the entire analysis (scitools) as well as custom scripts used will be made available on github.com/adeylab/organoid. All sequence read data for CIRM lines will be made available on dbGAP, with processed data available on GEO. Extended Data Fig 1. | Fluorescent microscopy analysis of transposome complex. a, Representative fluorescent images of DAPI stained fixed nuclei with Cy3 complexed transposomes without Pitstop 2 treatment. Scale bar is 10 μm. b, Representative fluorescent images of DAPI stained fixed nuclei with Cy3 complexed transposomes and treated with 70 μM Pitstop 2. Scale bar is 10 μm. c, 3D reconstruction of DAPI and ATAC-see signal showing blend projection function of Imaris Software. Nuclear blebbing as well as bursting of a 150 μM Pitstop 2 treated nuclei and diffusion of DAPI+ DNA into the environment is visualized in ...

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Section: Mainmentioning

confidence: 88%

Section: Mainmentioning

confidence: 99%

Section: Competing Financial Interestsmentioning

confidence: 99%

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Improved single-cell ATAC-seq reveals chromatin dynamics of in vitro corticogenesis

Mulqueen

DeRosa

Thornton

et al. 2019

Preprint

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“…Connecting regulatory DNA elements to target genes is a prerequisite to understanding transcriptional regulation. Cicero [32] predicts the interactions between cis-regulatory elements and the target genes using scCAS data. scATAC-pro generates the predicted interactions by running the module runCicero.…”

Section: Predicting Chromatin Interactions By Ciceromentioning

confidence: 99%

scATAC-pro: a comprehensive workbench for single-cell chromatin accessibility sequencing data

Yu¹,

Zhu

Chen³

et al. 2019

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AbstractSingle cell chromatin accessibility sequencing (scCAS) has become a powerful technology for understanding epigenetic heterogeneity of complex tissues. The development of several experimental protocols has led to a rapid accumulation of scCAS data. In contrast, there is a lack of open-source software tools for comprehensive processing, analysis and visualization of scCAS data generated using all existing experimental protocols. Here we present scATAC-pro for quality assessment, analysis and visualization of scCAS data. scATAC-pro provides flexible choice of methods for different data processing and analytical tasks, with carefully curated default parameters. A range of quality control metrics are computed for several key steps of the experimental protocol. scATAC-pro generates summary reports for both quality assessment and downstream analysis. It also provides additional utility functions for generating input files for various types of downstream analyses and data visualization. With the rapid accumulation of scCAS data, scATAC-pro will facilitate studies of epigenomic heterogeneity in healthy and diseased tissues.

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“…However, due to the bisulfite treatment, chromatin accessibility libraries suffer from the extremely low mapping percentage, and mutations would be acquired during the treatment. Additionally, scNMT-seq determines accessibility based on the methylation level rather than actual enrichment, rendering it less applicable for the integrative analysis using the pipeline like Coupled NMF, and the prediction of regulatory elements using the software such as CICERO 14 . More recently, two similar bimodal techniques, sci-CAR 15 and scCAT-seq 16 , are developed to jointly measure chromatin accessibility and gene expression within a single-cell.…”

Section: Introductionmentioning

confidence: 99%

Parallel Bimodal Single-cell Sequencing of Transcriptome and Chromatin Accessibility

Xing

Farran

Yao

et al. 2019

Preprint

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Accessibility, Co-accessibility. RUNNING TITLE: Multi-omic single-cell sequencing of gene expression and open chromatin SUMMARY We developed ASTAR-Seq (Assay for Single-cell Transcriptome and Accessibility Regions) integrated with automated microfluidic chips, which allows for parallel sequencing of transcriptome and chromatin accessibility within the same single-cell. Using ASTAR-Seq, we profiled 192 mESCs cultured in serum+LIF and 2i medium, 424 human cell lines including BJ, K562, JK1, and Jurkat, and 480 primary cells undergoing erythroblast differentiation. Integrative analysis using Coupled NMF identified the distinct subpopulations and uncovered sets of regulatory regions and the respective target genes determining their distinctions. Analysis of epigenetic regulomes further unravelled the key transcription factors responsible for the heterogeneity observed.

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Cicero Predicts cis-Regulatory DNA Interactions from Single-Cell Chromatin Accessibility Data

Cited by 654 publications

References 62 publications

Improved single-cell ATAC-seq reveals chromatin dynamics of in vitro corticogenesis

Improved single-cell ATAC-seq reveals chromatin dynamics of in vitro corticogenesis

scATAC-pro: a comprehensive workbench for single-cell chromatin accessibility sequencing data

Parallel Bimodal Single-cell Sequencing of Transcriptome and Chromatin Accessibility

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