Mechanisms linking cytoplasmic decay of translation-defective mRNA to transcriptional adaptation

Transcriptional adaptation (TA) is a genetic robustness mechanism through which mutant messenger RNA (mRNA) decay induces sequence-dependent up-regulation of so-called adapting genes. How cytoplasmically generated mRNA fragments affect nuclear transcription remains poorly understood. Using genome-wide CRISPR screens, we uncover ILF3 as an RNA binding protein connecting cytoplasmic mRNA decay and transcription during TA and show that it is required for a range of TA substrates. ILF3 is enriched at adapting genes' RNAs, and its artificial recruitment through dCas13 promotes gene expression. Using tiling oligonucleotide screens, we identify trigger RNA fragments that activate adapting genes when introduced into cells. Further functional dissection reveals a critical role for homology between trigger and target sequences. These findings enhance our molecular understanding of TA and inform the design of programmable oligonucleotides for gene expression augmentation.

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Publication Details

Journal
Science
Published
2026-02-12
DOI
https://doi.org/10.1126/science.aea1272
Citations
2
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
44.47
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article

Mechanisms linking cytoplasmic decay of translation-defective mRNA to transcriptional adaptation

Seth Goldman, Atharv Oak, Arash Latifkar, Jonathan S. Weissman et al.
2 citations
Science
RNA Research and Splicing
44.47
article

Mechanisms linking cytoplasmic decay of translation-defective mRNA to transcriptional adaptation

Seth Goldman, Atharv Oak, Arash Latifkar, Jonathan S. Weissman, Jingchuan Luo, Mohamed A. El-Brolosy, Yuancheng Ryan Lu, Reuben A. Saunders, Didier Y. R. Stainier, Amer Balabaki, An Hoang, Jeremy Guez, Konrad J. Karczewski, Yassine Damergi, André Fischer, Troy W. Whitfield
article en
2 citations

Abstract

Transcriptional adaptation (TA) is a genetic robustness mechanism through which mutant messenger RNA (mRNA) decay induces sequence-dependent up-regulation of so-called adapting genes. How cytoplasmically generated mRNA fragments affect nuclear transcription remains poorly understood. Using genome-wide CRISPR screens, we uncover ILF3 as an RNA binding protein connecting cytoplasmic mRNA decay and transcription during TA and show that it is required for a range of TA substrates. ILF3 is enriched at adapting genes' RNAs, and its artificial recruitment through dCas13 promotes gene expression. Using tiling oligonucleotide screens, we identify trigger RNA fragments that activate adapting genes when introduced into cells. Further functional dissection reveals a critical role for homology between trigger and target sequences. These findings enhance our molecular understanding of TA and inform the design of programmable oligonucleotides for gene expression augmentation.

ScienceVol. 391(6786)
Broad Institute (US), Howard Hughes Medical Institute (US), Harvard University (US), Harvard University Press (US), Foundation Center (US), Massachusetts General Hospital (US), Max Planck Institute for Heart and Lung Research (DE), Novo Nordisk (United States) (US), Whitehead Institute for Biomedical Research (US), Massachusetts Institute of Technology (US)
Openalex Percentile: Top 0%
RNA Research and Splicing
44.47
DOIOpen Access PDFOpenAlex
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