Beyond chromatin accessibility: bulk ATAC-seq as an integrative assay to portray genomes and epigenomes.

Overview

1. Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM), 34298 Montpellier, France
2. Equipe labélisée Ligue Contre le Cancer, 75013 Paris, France

Abstract

Assay for transposase-accessible chromatin using sequencing (ATAC-seq) is a cornerstone for epigenomic profiling, yet its potential for genomic characterization remains poorly explored. Here, we systematically benchmarked bulk ATAC-seq against whole-genome sequencing (WGS) to assess its capacity for detecting small variants, copy number variations (CNVs), telomere-associated repeat content, and mitochondrial single-nucleotide polymorphisms in cancer cells. Using paired datasets from patient-derived melanoma cell lines and from TCGA primary brain tumors, we demonstrated that ATAC-seq achieves high precision in small variants detection within accessible regions supporting cohort-scale genotyping and genetic stratification, robustly resolves CNVs in the nuclear genome, and supports high-coverage mitogenome profiling, with strong concordance to WGS at standard sequencing depths. Notably, we present the first systematic evaluation of telomere-associated repeat content by ATAC-seq, revealing its untapped potential for studying genome stability. By bridging genomic and epigenomic insights into a single genome-wide approach, bulk ATAC-seq emerges as a cost-effective and versatile tool poised to transform cancer research and to support integrative molecular profiling in clinical settings.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

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Data

Datasets cited

• geo:GSE134432 — at NCBI GEO; found in “Data availability”

Data availability

Matched raw ATAC-seq, H3K27ac ChIP-seq, RNA-seq, and WGS data from the A375, MM001, MM011, MM029, MM031, MM047, MM057, MM074, MM087, and MM099 patient-derived melanoma cell lines were obtained from European Genome-Phenome Archive (EGAS00001004136) and Gene Expression Omnibus (GSE134432 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE134432), GSE142238 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE142238), and GSE159965 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE159965)). Matched aligned ATAC-seq and WGS from TCGA GBM and LGG cohorts were downloaded from The National Cancer Institute (NCI) Genomic Data Commons (GDC) portal. The code enabling to reproduce all the analyses performed in this study is hosted on Zenodo with accession 10.5281/zenodo.14871223.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Versions

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Version 2, 28 September 2026

• Funding: added Institut National de la Santé et de la Recherche Médicale; Fondation pour la Recherche Médicale; Ligue Contre le Cancer: INCa INSERM DGOS 12553; Division of Arctic Sciences

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 5 authors, 12 MeSH terms, 94 references.

Cite

This paper

Toumi, I., Kham, C., Stuani, L., Le Cam, L., & Roux, P.-F. (2026). Beyond chromatin accessibility: bulk ATAC-seq as an integrative assay to portray genomes and epigenomes. NAR genomics and bioinformatics, 8(2), lqag046. https://doi.org/10.1093/nargab/lqag046

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