Transcriptional neighborhoods regulate transcript isoform lengths and expression levels

Aaron N. Brooks, Amanda L. Hughes, Sandra Clauder-Münster, Leslie A. Mitchell, Jef D. Boeke, Lars M. Steinmetz

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Sequence features of genes and their flanking regulatory regions are determinants of RNA transcript isoform expression and have been used as context-independent plug-and-play modules in synthetic biology. However, genetic context—including the adjacent transcriptional environment—also influences transcript isoform expression levels and boundaries. We used synthetic yeast strains with stochastically repositioned genes to systematically disentangle the effects of sequence and context. Profiling 120 million full-length transcript molecules across 612 genomic perturbations, we observed sequence-independent alterations to gene expression levels and transcript isoform boundaries that were influenced by neighboring transcription. We identified features of transcriptional context that could predict these alterations and used these features to engineer a synthetic circuit where transcript length was controlled by neighboring transcription. This demonstrates how positional context can be leveraged in synthetic genome engineering.

    Original languageEnglish (US)
    Pages (from-to)1000-1005
    Number of pages6
    JournalScience
    Volume375
    Issue number6584
    DOIs
    StatePublished - Mar 4 2022

    ASJC Scopus subject areas

    • General

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