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Quantification, Dynamic Visualization, and Validation of Bias in ATAC-Seq Data with ataqv.

ABSTRACT: The assay for transposase-accessible chromatin using sequencing (ATAC-seq) has become the preferred method for mapping chromatin accessibility due to its time and input material efficiency. However, it can be difficult to evaluate data quality and identify sources of technical bias across samples. Here, we present ataqv, a computational toolkit for efficiently measuring, visualizing, and comparing quality control (QC) results across samples and experiments. We use ataqv to analyze 2,009 public ATAC-seq datasets; their QC metrics display a 10-fold range. Tn5 dosage experiments and statistical modeling show that technical variation in the ratio of Tn5 transposase to nuclei and sequencing flowcell density induces systematic bias in ATAC-seq data by changing the enrichment of reads across functional genomic annotations including promoters, enhancers, and transcription-factor-bound regions, with the notable exception of CTCF. ataqv can be integrated into existing computational pipelines and is freely available at https://github.com/ParkerLab/ataqv/.

SUBMITTER: Orchard P

PROVIDER: S-EPMC8245295 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Quantification, dynamic visualization, and validation of bias in ATAC-seq data with ataqv

Project description:The assay for transposase-accessible chromatin using sequencing (ATAC-seq) has become the preferred method for mapping chromatin accessibility, due to its simplicity, speed, and low input material requirements. However, it can be difficult to evaluate data quality, particularly when processing many samples. Here, we present ataqv, a computational toolkit for efficiently measuring, visualizing, and comparing ATAC-seq quality control results. We perform controlled ATAC-seq experiments and utilize ataqv to show that the ratio of Tn5 transposase to nuclei and sequencing flowcell cluster density induce reproducible technical bias in ATAC-seq results, significantly changing the fragment length distribution and enrichment of reads in promoter and enhancer chromatin states.

2020-03-23 | GSE130450 | GEO

Quantification, dynamic visualization, and validation of bias in ATAC-seq data with ataqv

Project description:Quantification, dynamic visualization, and validation of bias in ATAC-seq data with ataqv

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GUAVA: A Graphical User Interface for the Analysis and Visualization of ATAC-seq Data.

Project description:Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq) is a powerful genomic technology that is used for the global mapping and analysis of open chromatin regions. However, for users to process and analyze such data they either have to use a number of complicated bioinformatic tools or attempt to use the currently available ATAC-seq analysis software, which are not very user friendly and lack visualization of the ATAC-seq results. Because of these issues, biologists with minimal bioinformatics background who wish to process and analyze their own ATAC-seq data by themselves will find these tasks difficult and ultimately will need to seek help from bioinformatics experts. Moreover, none of the available tools provide complete solution for ATAC-seq data analysis. Therefore, to enable non-programming researchers to analyze ATAC-seq data on their own, we developed a tool called Graphical User interface for the Analysis and Visualization of ATAC-seq data (GUAVA). GUAVA is a standalone software that provides users with a seamless solution from beginning to end including adapter trimming, read mapping, the identification and differential analysis of ATAC-seq peaks, functional annotation, and the visualization of ATAC-seq results. We believe GUAVA will be a highly useful and time-saving tool for analyzing ATAC-seq data for biologists with minimal or no bioinformatics background. Since GUAVA can also operate through command-line, it can easily be integrated into existing pipelines, thus providing flexibility to users with computational experience.

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ATAC-seq with unique molecular identifiers improves quantification and footprinting.

Project description:ATAC-seq (Assay for Transposase-Accessible Chromatin with high-throughput sequencing) provides an efficient way to analyze nucleosome-free regions and has been applied widely to identify transcription factor footprints. Both applications rely on the accurate quantification of insertion events of the hyperactive transposase Tn5. However, due to the presence of the PCR amplification, it is impossible to accurately distinguish independently generated identical Tn5 insertion events from PCR duplicates using the standard ATAC-seq technique. Removing PCR duplicates based on mapping coordinates introduces increasing bias towards highly accessible chromatin regions. To overcome this limitation, we establish a UMI-ATAC-seq technique by incorporating unique molecular identifiers (UMIs) into standard ATAC-seq procedures. UMI-ATAC-seq can rescue about 20% of reads that are mistaken as PCR duplicates in standard ATAC-seq in our study. We demonstrate that UMI-ATAC-seq could more accurately quantify chromatin accessibility and significantly improve the sensitivity of identifying transcription factor footprints. An analytic pipeline is developed to facilitate the application of UMI-ATAC-seq, and it is available at https://github.com/tzhu-bio/UMI-ATAC-seq .

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ShinyArchR.UiO: user-friendly,integrative and open-source tool for visualization of single-cell ATAC-seq data using ArchR.

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Detecting Differential Transcription Factor Activity from ATAC-Seq Data.

Project description:Transcription factors are managers of the cellular factory, and key components to many diseases. Many non-coding single nucleotide polymorphisms affect transcription factors, either by directly altering the protein or its functional activity at individual binding sites. Here we first briefly summarize high-throughput approaches to studying transcription factor activity. We then demonstrate, using published chromatin accessibility data (specifically ATAC-seq), that the genome-wide profile of TF recognition motifs relative to regions of open chromatin can determine the key transcription factor altered by a perturbation. Our method of determining which TFs are altered by a perturbation is simple, is quick to implement, and can be used when biological samples are limited. In the future, we envision that this method could be applied to determine which TFs show altered activity in response to a wide variety of drugs and diseases.

| S-EPMC6099720 | biostudies-literature

Reproducible inference of transcription factor footprints in ATAC-seq and DNase-seq datasets using protocol-specific bias modeling.

Project description:BackgroundDNase-seq and ATAC-seq are broadly used methods to assay open chromatin regions genome-wide. The single nucleotide resolution of DNase-seq has been further exploited to infer transcription factor binding sites (TFBSs) in regulatory regions through footprinting. Recent studies have demonstrated the sequence bias of DNase I and its adverse effects on footprinting efficiency. However, footprinting and the impact of sequence bias have not been extensively studied for ATAC-seq.ResultsHere, we undertake a systematic comparison of the two methods and show that a modification to the ATAC-seq protocol increases its yield and its agreement with DNase-seq data from the same cell line. We demonstrate that the two methods have distinct sequence biases and correct for these protocol-specific biases when performing footprinting. Despite the differences in footprint shapes, the locations of the inferred footprints in ATAC-seq and DNase-seq are largely concordant. However, the protocol-specific sequence biases in conjunction with the sequence content of TFBSs impact the discrimination of footprint from the background, which leads to one method outperforming the other for some TFs. Finally, we address the depth required for reproducible identification of open chromatin regions and TF footprints.ConclusionsWe demonstrate that the impact of bias correction on footprinting performance is greater for DNase-seq than for ATAC-seq and that DNase-seq footprinting leads to better performance. It is possible to infer concordant footprints by using replicates, highlighting the importance of reproducibility assessment. The results presented here provide an overview of the advantages and limitations of footprinting analyses using ATAC-seq and DNase-seq.

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scDAPA: detection and visualization of dynamic alternative polyadenylation from single cell RNA-seq data.

Project description:MotivationAlternative polyadenylation (APA) plays a key post-transcriptional regulatory role in mRNA stability and functions in eukaryotes. Single cell RNA-seq (scRNA-seq) is a powerful tool to discover cellular heterogeneity at gene expression level. Given 3' enriched strategy in library construction, the most commonly used scRNA-seq protocol-10× Genomics enables us to improve the study resolution of APA to the single cell level. However, currently there is no computational tool available for investigating APA profiles from scRNA-seq data.ResultsHere, we present a package scDAPA for detecting and visualizing dynamic APA from scRNA-seq data. Taking bam/sam files and cell cluster labels as inputs, scDAPA detects APA dynamics using a histogram-based method and the Wilcoxon rank-sum test, and visualizes candidate genes with dynamic APA. Benchmarking results demonstrated that scDAPA can effectively identify genes with dynamic APA among different cell groups from scRNA-seq data.Availability and implementationThe scDAPA package is implemented in Shell and R, and is freely available at https://scdapa.sourceforge.io.Supplementary informationSupplementary data are available at Bioinformatics online.

| S-EPMC8215916 | biostudies-literature

Comparison of differential accessibility analysis strategies for ATAC-seq data.

Project description:ATAC-seq is widely used to measure chromatin accessibility and identify open chromatin regions (OCRs). OCRs usually indicate active regulatory elements in the genome and are directly associated with the gene regulatory network. The identification of differential accessibility regions (DARs) between different biological conditions is critical in determining the differential activity of regulatory elements. Differential analysis of ATAC-seq shares many similarities with differential expression analysis of RNA-seq data. However, the distribution of ATAC-seq signal intensity is different from that of RNA-seq data, and higher sensitivity is required for DARs identification. Many different tools can be used to perform differential analysis of ATAC-seq data, but a comprehensive comparison and benchmarking of these methods is still lacking. Here, we used simulated datasets to systematically measure the sensitivity and specificity of six different methods. We further discussed the statistical and signal density cut-offs in the differential analysis of ATAC-seq by applying them to real data. Batch effects are very common in high-throughput sequencing experiments. We illustrated that batch-effect correction can dramatically improve sensitivity in the differential analysis of ATAC-seq data. Finally, we developed a user-friendly package, BeCorrect, to perform batch effect correction and visualization of corrected ATAC-seq signals in a genome browser.

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Comprehensive analysis of single cell ATAC-seq data with SnapATAC.

Project description:Identification of the cis-regulatory elements controlling cell-type specific gene expression patterns is essential for understanding the origin of cellular diversity. Conventional assays to map regulatory elements via open chromatin analysis of primary tissues is hindered by sample heterogeneity. Single cell analysis of accessible chromatin (scATAC-seq) can overcome this limitation. However, the high-level noise of each single cell profile and the large volume of data pose unique computational challenges. Here, we introduce SnapATAC, a software package for analyzing scATAC-seq datasets. SnapATAC dissects cellular heterogeneity in an unbiased manner and map the trajectories of cellular states. Using the Nyström method, SnapATAC can process data from up to a million cells. Furthermore, SnapATAC incorporates existing tools into a comprehensive package for analyzing single cell ATAC-seq dataset. As demonstration of its utility, SnapATAC is applied to 55,592 single-nucleus ATAC-seq profiles from the mouse secondary motor cortex. The analysis reveals ~370,000 candidate regulatory elements in 31 distinct cell populations in this brain region and inferred candidate cell-type specific transcriptional regulators.

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