Precision RNAi using synthetic shRNAmir target sites

Hoffmann, Thomas; Hörmann, Alexandra; Corcokovic, Maja; Zmajkovic, Jakub; Hinterndorfer, Matthias; Salkanovic, Jasko; Spreitzer, Fiona; Köferle, Anna; Gitschtaler, Katrin; Popa, Alexandra; Oberndorfer, Sarah; Andersch, Florian; Schaefer, Markus; Fellner, Michaela; Budano, Nicole; Ruppert, Jan Gustav; Chetta, Paolo; Wurm, Melanie; Zuber, Johannes; Neumüller, Ralph A.

doi:10.7554/elife.84792.3

Cited by 2 publications

(2 citation statements)

References 40 publications

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“…We also tested whether MEK1/2 inhibition brings about the activation of this pathway in other tumors with a hyperactive RAS-RAF-MEK axis. We found that colon cancer cell lines treated with trametinib ( 54 – 56 ) showed the consistent induction of ERVs, ELF3 and IRF1, as well as the activation of an IFN response (fig. S6, C and D).…”

Section: Resultsmentioning

confidence: 87%

“…Datasets are available in the Gene Expression Omnibus (GEO) database ( http://www.ncbi.nlm.nih.gov/geo ) under the accession number GSE238200. Additional RNA-seq datasets were obtained from European Nucleotide Archive (ENA) database ( http://www.ebi.ac.uk/ena/ ) under the accession number PRJEB25806 ( 17 ) and from GEO database ( http://www.ncbi.nlm.nih.gov/geo ) under accession numbers GSE218404, GSE118548, and GSE78519 ( 54 – 56 ).…”

Section: Methodsmentioning

confidence: 99%

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Activation of endogenous retroviruses and induction of viral mimicry by MEK1/2 inhibition in pancreatic cancer

Cortesi,

Gandolfi,

Arco

et al. 2024

Sci. Adv.

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While pancreatic ductal adenocarcinomas (PDACs) are addicted to KRAS-activating mutations, inhibitors of downstream KRAS effectors, such as the MEK1/2 kinase inhibitor trametinib, are devoid of therapeutic effects. However, the extensive rewiring of regulatory circuits driven by the attenuation of the KRAS pathway may induce vulnerabilities of therapeutic relevance. An in-depth molecular analysis of the transcriptional and epigenomic alterations occurring in PDAC cells in the initial hours after MEK1/2 inhibition by trametinib unveiled the induction of endogenous retroviruses (ERVs) escaping epigenetic silencing, leading to the production of double-stranded RNAs and the increased expression of interferon (IFN) genes. We tracked ERV activation to the early induction of the transcription factor ELF3, which extensively bound and activated nonsilenced retroelements and synergized with IRF1 (interferon regulatory factor 1) in the activation of IFNs and IFN-stimulated genes. Trametinib-induced viral mimicry in PDAC may be exploited in the rational design of combination therapies in immuno-oncology.

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Section: Resultsmentioning

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Activation of endogenous retroviruses and induction of viral mimicry by MEK1/2 inhibition in pancreatic cancer

Cortesi,

Gandolfi,

Arco

et al. 2024

Sci. Adv.

View full text Add to dashboard Cite

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Manipulating and studying gene function in human pluripotent stem cell models

Balmas,

Sozza,

Bottini

et al. 2023

FEBS Letters

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Human pluripotent stem cells (hPSCs) are uniquely suited to study human development and disease and promise to revolutionize regenerative medicine. These applications rely on robust methods to manipulate gene function in hPSC models. This comprehensive review aims to both empower scientists approaching the field and update experienced stem cell biologists. We begin by highlighting challenges with manipulating gene expression in hPSCs and their differentiated derivatives, and relevant solutions (transfection, transduction, transposition, and genomic safe harbor editing). We then outline how to perform robust constitutive or inducible loss‐, gain‐, and change‐of‐function experiments in hPSCs models, both using historical methods (RNA interference, transgenesis, and homologous recombination) and modern programmable nucleases (particularly CRISPR/Cas9 and its derivatives, i.e., CRISPR interference, activation, base editing, and prime editing). We further describe extension of these approaches for arrayed or pooled functional studies, including emerging single‐cell genomic methods, and the related design and analytical bioinformatic tools. Finally, we suggest some directions for future advancements in all of these areas. Mastering the combination of these transformative technologies will empower unprecedented advances in human biology and medicine.

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Precision RNAi using synthetic shRNAmir target sites

Cited by 2 publications

References 40 publications

Activation of endogenous retroviruses and induction of viral mimicry by MEK1/2 inhibition in pancreatic cancer

Activation of endogenous retroviruses and induction of viral mimicry by MEK1/2 inhibition in pancreatic cancer

Manipulating and studying gene function in human pluripotent stem cell models

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