دورية أكاديمية
أعرض في EDS

Bidirectional promoter activity from expression cassettes can drive off-target repression of neighboring gene translation.

التفاصيل البيبلوغرافية
العنوان: Bidirectional promoter activity from expression cassettes can drive off-target repression of neighboring gene translation.
المؤلفون: Powers EN; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States., Chan C; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States., Doron-Mandel E; Department of Biological Sciences, Columbia University, New York, United States., Llacsahuanga Allcca L; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States., Kim Kim J; Department of Biological Sciences, Columbia University, New York, United States., Jovanovic M; Department of Biological Sciences, Columbia University, New York, United States., Brar GA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.; California Institute for Quantitative Biosciences (QB3), University of California, Berkley, Berkley, United States.; Center for Computational Biology, University of California, Berkeley, Berkeley, United States.
المصدر: ELife [Elife] 2022 Dec 12; Vol. 11. Date of Electronic Publication: 2022 Dec 12.
نوع المنشور: Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: eLife Sciences Publications, Ltd Country of Publication: England NLM ID: 101579614 Publication Model: Electronic Cited Medium: Internet ISSN: 2050-084X (Electronic) Linking ISSN: 2050084X NLM ISO Abbreviation: Elife Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Cambridge, UK : eLife Sciences Publications, Ltd., 2012-
مواضيع طبية MeSH: Saccharomyces cerevisiae*/genetics , Saccharomyces cerevisiae*/metabolism , Saccharomyces cerevisiae Proteins*/genetics , Saccharomyces cerevisiae Proteins*/metabolism, Humans ; Promoter Regions, Genetic ; Protein Biosynthesis ; DEAD-box RNA Helicases/metabolism
مستخلص: Targeted selection-based genome-editing approaches have enabled many fundamental discoveries and are used routinely with high precision. We found, however, that replacement of DBP1 with a common selection cassette in budding yeast led to reduced expression and function for the adjacent gene, MRP51 , despite all MRP51 coding and regulatory sequences remaining intact. Cassette-induced repression of MRP51 drove all mutant phenotypes detected in cells deleted for DBP1 . This behavior resembled the 'neighboring gene effect' (NGE), a phenomenon of unknown mechanism whereby cassette insertion at one locus reduces the expression of a neighboring gene. Here, we leveraged strong off-target mutant phenotypes resulting from cassette replacement of DBP1 to provide mechanistic insight into the NGE. We found that the inherent bidirectionality of promoters, including those in expression cassettes, drives a divergent transcript that represses MRP51 through combined transcriptional interference and translational repression mediated by production of a long undecoded transcript isoform (LUTI). Divergent transcript production driving this off-target effect is general to yeast expression cassettes and occurs ubiquitously with insertion. Despite this, off-target effects are often naturally prevented by local sequence features, such as those that terminate divergent transcripts between the site of cassette insertion and the neighboring gene. Thus, cassette-induced off-target effects can be eliminated by the insertion of transcription terminator sequences into the cassette, flanking the promoter. Because the driving features of this off-target effect are broadly conserved, our study suggests it should be considered in the design and interpretation of experiments using integrated expression cassettes in other eukaryotic systems, including human cells.
Competing Interests: EP, CC, ED, LL, JK, MJ, GB No competing interests declared
(© 2022, Powers et al.)
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معلومات مُعتمدة: R35 GM128802 United States GM NIGMS NIH HHS; R35 GM134886 United States GM NIGMS NIH HHS
فهرسة مساهمة: Keywords: S. cerevisiae; alternative transcripts; bidirectional transcription; chromosomes; gene expression; genetics; genome editing; genomics; neighboring gene effect; transcriptional interference
سلسلة جزيئية: GEO GSE207267; GSE207189; GSE121189; GSE111255
المشرفين على المادة: EC 3.6.1.- (DBP1 protein, S cerevisiae)
0 (Saccharomyces cerevisiae Proteins)
EC 3.6.4.13 (DEAD-box RNA Helicases)
تواريخ الأحداث: Date Created: 20221212 Date Completed: 20221216 Latest Revision: 20240704
رمز التحديث: 20240704
مُعرف محوري في PubMed: PMC9754628
DOI: 10.7554/eLife.81086
PMID: 36503721
قاعدة البيانات: MEDLINE
الوصف
تدمد:2050-084X
DOI:10.7554/eLife.81086