Epigenomic reprogramming of repetitive noncoding RNAs and IFN-stimulated genes by mutant KRAS
ABSTRACT RAS genes are the most frequently mutated oncogenes in cancer. However, the effects of oncogenic RAS signaling on the noncoding transcriptome are unclear. We analyzed the transcriptomes of human airway epithelial cells transformed with mutant KRAS to define the landscape of KRAS-regulated n...
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Published in | bioRxiv |
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Main Authors | , , , , , , , , , , , , , |
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Cold Spring Harbor Laboratory Press
04.11.2020
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Abstract | ABSTRACT RAS genes are the most frequently mutated oncogenes in cancer. However, the effects of oncogenic RAS signaling on the noncoding transcriptome are unclear. We analyzed the transcriptomes of human airway epithelial cells transformed with mutant KRAS to define the landscape of KRAS-regulated noncoding RNAs. We found that oncogenic KRAS upregulates noncoding transcripts throughout the genome, many of which arise from transposable elements. These repetitive noncoding RNAs exhibit differential RNA editing in single cells, are released in extracellular vesicles, and are known targets of KRAB zinc-finger proteins, which are broadly down-regulated in mutant KRAS cells and lung adenocarcinomas. Moreover, mutant KRAS induces IFN-stimulated genes through both epigenetic and RNA-based mechanisms. Our results reveal that mutant KRAS remodels the noncoding transcriptome through epigenomic reprogramming, expanding the scope of genomic elements regulated by this fundamental signaling pathway and revealing how mutant KRAS induces an intrinsic IFN-stimulated gene signature often seen in ADAR-dependent cancers. Competing Interest Statement The authors have declared no competing interest. |
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AbstractList | ABSTRACT RAS genes are the most frequently mutated oncogenes in cancer. However, the effects of oncogenic RAS signaling on the noncoding transcriptome are unclear. We analyzed the transcriptomes of human airway epithelial cells transformed with mutant KRAS to define the landscape of KRAS-regulated noncoding RNAs. We found that oncogenic KRAS upregulates noncoding transcripts throughout the genome, many of which arise from transposable elements. These repetitive noncoding RNAs exhibit differential RNA editing in single cells, are released in extracellular vesicles, and are known targets of KRAB zinc-finger proteins, which are broadly down-regulated in mutant KRAS cells and lung adenocarcinomas. Moreover, mutant KRAS induces IFN-stimulated genes through both epigenetic and RNA-based mechanisms. Our results reveal that mutant KRAS remodels the noncoding transcriptome through epigenomic reprogramming, expanding the scope of genomic elements regulated by this fundamental signaling pathway and revealing how mutant KRAS induces an intrinsic IFN-stimulated gene signature often seen in ADAR-dependent cancers. Competing Interest Statement The authors have declared no competing interest. |
Author | Fernandes, Jason Reggiardo, Roman E Ozen, Mehmet Demirci, Utkan Marinov, Georgi Sreelakshmi Velandi Maroli Kim, Daniel H Carrillo, David Lamontagne, Erin Collisson, Eric Whitehead, Lila Kim, Eejung Haley Halasz Malik, Shivani |
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SubjectTerms | Epigenetics Epithelial cells Gene expression Interferon K-Ras protein Mutants RNA editing Signal transduction Transcriptomes Zinc finger proteins |
Title | Epigenomic reprogramming of repetitive noncoding RNAs and IFN-stimulated genes by mutant KRAS |
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