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

Turkalj, Sven; Jakobsen, Niels Asger; Groom, Angus; Metzner, Marlen; Riva, Simone G.; Gur, Eran; Usukhbayar, Batchimeg; Salazar, Mirian Angulo; Hentges, Lance D.; Mickute, Gerda; Clark, Kevin D.; Sopp, P.; Davies, James O. J.; Hughes, Jim R.; Vyas, Paresh

doi:10.1016/j.stem.2023.04.012

Cited by 8 publications

(13 citation statements)

References 116 publications

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“…In samples with multiple mutations, the pattern of mutational co-occurrence was used to determine clonal structures and assign a clonal identity to each cell as previously described. 106,107 In samples where mutations were mutually exclusive, such as in samples…”

Section: Methodsmentioning

confidence: 99%

Selective advantage of mutant stem cells in clonal hematopoiesis occurs by attenuating the deleterious effects of inflammation and aging

Jakobsen,

Turkalj,

Zeng

et al. 2023

Preprint

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Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSC) acquire mutations in genes, includingDNMT3AandTET2, conferring a competitive advantage through a mechanism that remains unclear. To gain insight into how CH mutations enable gradual clonal expansion, we used single-cell multi-omics with high-fidelity genotyping on CH bone marrow samples. Most of the selective advantage of mutant cells occurs within HSCs.DNMT3AandTET2-mutant clones expand further in early progenitors, whileTET2mutations accelerate myeloid maturation in a dose-dependent manner. Unexpectedly, both mutant and non-mutant HSCs from CH samples are enriched for inflammatory and aging transcriptomic signatures, compared to HSC from non-CH samples, revealing a non-cell autonomous mechanism. However,DNMT3AandTET2-mutant HSCs have an attenuated inflammatory response relative to wild-type HSCs within the same sample. Our data support a model whereby CH clones are gradually selected because they are more resistant to the deleterious impact of inflammation and aging.

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Section: Methodsmentioning

confidence: 99%

Selective advantage of mutant stem cells in clonal hematopoiesis occurs by attenuating the deleterious effects of inflammation and aging

Jakobsen,

Turkalj,

Zeng

et al. 2023

Preprint

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“…Emerging single‐cell approaches coupling somatic genotypes with cellular readouts are potent tools to describe clonal complexity 180 . Complementing these technologies, our group recently integrated clonal readout with chromatin accessibility profiling at single‐cell resolution, linking genetic and epigenetic disease evolution 181 . Going forward, this approach will elucidate clone‐specific epigenetic mechanisms underlying disease relapse.…”

Section: Challenges Ahead: How To Overcome Them?mentioning

confidence: 99%

An Overview of Targeted Therapies in Acute Myeloid Leukemia

2023

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Acute myeloid leukemia (AML) is the most aggressive adult leukemia, characterized by clonal differentiation arrest of progenitor or precursor hematopoietic cells. Intense preclinical and clinical research has led to regulatory approval of several targeted therapeutics, administered either as single agents or as combination therapies. However, the majority of patients still face a poor prognosis and disease relapse frequently occurs due to selection of therapy-resistant clones. Hence, more effective novel therapies, most likely as innovative, rational combination therapies, are urgently needed. Chromosomal aberrations, gene mutations, and epigenetic alterations drive AML pathogenesis but concurrently provide vulnerabilities to specifically target leukemic cells. Other molecules, either aberrantly active and/or overexpressed in leukemic stem cells, may also be leveraged for therapeutic benefit. This concise review of targeted therapies for AML treatment, which are either approved or are being actively investigated in clinical trials or recent preclinical studies, provides a flavor of the direction of travel, but also highlights the current challenges in AML treatment.

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“…The main advantage of GTAC over classical scATAC-seq is the amplification of multiple genomic loci harboring mutations, in parallel with amplification of open chromatin fragments. 1 This is achieved by adding target-specific primers ( part 3 , point 34) to the PCR ( part 3 , point 36).…”

Section: Before You Beginmentioning

confidence: 99%

“…A schematic overview is shown in Figure 3 . Note: A list of all pre-amplification and nested genotyping primers that we have previously validated for GTAC applications 1 is provided in Table S1 . We advise to use some of these primer pairs as positive controls in points 12 and 13.…”

Section: Before You Beginmentioning

confidence: 99%

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A protocol for simultaneous high-sensitivity genotyping and chromatin accessibility profiling in single cells

Turkalj,

Jakobsen,

Groom

et al. 2023

STAR Protocols

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

Cited by 8 publications

References 116 publications

Selective advantage of mutant stem cells in clonal hematopoiesis occurs by attenuating the deleterious effects of inflammation and aging

Selective advantage of mutant stem cells in clonal hematopoiesis occurs by attenuating the deleterious effects of inflammation and aging

An Overview of Targeted Therapies in Acute Myeloid Leukemia

A protocol for simultaneous high-sensitivity genotyping and chromatin accessibility profiling in single cells

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