GTAC enables parallel genotyping of multiple genomic loci with chromatin accessibility profiling in single cells

Understanding clonal evolution and cancer development requires experimental approaches for characterizing the consequences of somatic mutations on gene regulation. However, no methods currently exist that efficiently link high-content chromatin accessibility with high-confidence genotyping in single...

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Bibliographic Details
Published in:Cell stem cell Vol. 30; no. 5; p. 722
Main Authors: Turkalj, Sven, Jakobsen, Niels Asger, Groom, Angus, Metzner, Marlen, Riva, Simone G, Gür, E Ravza, Usukhbayar, Batchimeg, Salazar, Mirian Angulo, Hentges, Lance D, Mickute, Gerda, Clark, Kevin, Sopp, Paul, Davies, James O J, Hughes, Jim R, Vyas, Paresh
Format: Journal Article
Language:English
Published: United States 04.05.2023
Subjects:
Chromatin
Gene Expression Regulation
Genomics
Genotype
Humans
Leukemia, Myeloid, Acute
Transposases - genetics
Transposases - metabolism
leukemia stem cells
single-cell ATAC-seq
acute myeloid leukemia
chromatin accessibility
epigenomics
single-cell technologies
cancer evolution
somatic mutation
clonal tracking
tumor heterogeneity
ISSN:1875-9777, 1875-9777
Online Access:Get more information
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Summary:Understanding clonal evolution and cancer development requires experimental approaches for characterizing the consequences of somatic mutations on gene regulation. However, no methods currently exist that efficiently link high-content chromatin accessibility with high-confidence genotyping in single cells. To address this, we developed Genotyping with the Assay for Transposase-Accessible Chromatin (GTAC), enabling accurate mutation detection at multiple amplified loci, coupled with robust chromatin accessibility readout. We applied GTAC to primary acute myeloid leukemia, obtaining high-quality chromatin accessibility profiles and clonal identities for multiple mutations in 88% of cells. We traced chromatin variation throughout clonal evolution, showing the restriction of different clones to distinct differentiation stages. Furthermore, we identified switches in transcription factor motif accessibility associated with a specific combination of driver mutations, which biased transformed progenitors toward a leukemia stem cell-like chromatin state. GTAC is a powerful tool to study clonal heterogeneity across a wide spectrum of pre-malignant and neoplastic conditions.
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ISSN:1875-9777
1875-9777
DOI:10.1016/j.stem.2023.04.012