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Enhancer mutations modulate the severity of chemotherapy-induced myelosuppression
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0001-9251-1059
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.ORCID iD: 0000-0002-1648-6426
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2024 (English)In: Life Science Alliance, E-ISSN 2575-1077, Vol. 7, no 3, p. e202302244-e202302244Article in journal (Refereed) Published
Abstract [en]

Non-small cell lung cancer is often diagnosed at advanced stages, and many patients are still treated with classical chemotherapy. The unselective nature of chemotherapy often results in severe myelosuppression. Previous studies showed that protein-coding mutations could not fully explain the predisposition to myelosuppression. Here, we investigate the possible role of enhancer mutations in myelosuppression susceptibility. We produced transcriptome and promoter-interaction maps (using HiCap) of three blood stem-like cell lines treated with carboplatin or gemcitabine. Taking advantage of publicly available enhancer datasets, we validated HiCap results in silico and in living cells using epigenetic CRISPR technology. We also developed a network approach for interactome analysis and detection of differentially interacting genes. Differential interaction analysis provided additional information on relevant genes and pathways for myelosuppression compared with differential gene expression analysis at the bulk level. Moreover, we showed that enhancers of differentially interacting genes are highly enriched for variants associated with differing levels of myelosuppression. Altogether, our work represents a prominent example of integrative transcriptome and gene regulatory datasets analysis for the functional annotation of noncoding mutations.

Place, publisher, year, edition, pages
Life Science Alliance, LLC , 2024. Vol. 7, no 3, p. e202302244-e202302244
National Category
Biochemistry Molecular Biology Genetics and Genomics
Identifiers
URN: urn:nbn:se:kth:diva-342369DOI: 10.26508/lsa.202302244PubMedID: 38228368Scopus ID: 2-s2.0-85182610147OAI: oai:DiVA.org:kth-342369DiVA, id: diva2:1828509
Funder
EU, Horizon 2020, 860002Swedish Cancer SocietySwedish Childhood Cancer FoundationSwedish Research Council, ALF Grant region ÖstergötlandSwedish Research Council, 78081
Note

QC 20240123

Available from: 2024-01-17 Created: 2024-01-17 Last updated: 2025-02-20Bibliographically approved

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Zhigulev, ArtemiiNorberg, ZandraCordier, JulieSpalinskas, RapolasBassereh, HassanPradhananga, SailendraSahlén, Pelin

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Zhigulev, ArtemiiNorberg, ZandraCordier, JulieSpalinskas, RapolasBassereh, HassanPradhananga, SailendraGréen, HenrikSahlén, Pelin
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Gene TechnologyScience for Life Laboratory, SciLifeLab
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