Enhancer mutations modulate the severity of chemotherapy-induced myelosuppression.

Zhigulev A, Norberg Z, Cordier J, Spalinskas R, Bassereh H, Björn N, Pradhananga S, Gréen H, Sahlén P

Life Sci. Alliance 7 (3) - [2024-03-00; online 2024-01-16]

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.

NGI Short read [Service]

NGI Stockholm (Genomics Production) [Service]

National Genomics Infrastructure [Service]

PubMed 38228368

DOI 10.26508/lsa.202302244

Crossref 10.26508/lsa.202302244

pmc: PMC10796589
pii: 7/3/e202302244

Publications 9.5.0