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RNA exosome-dependent transcriptional adaptation masks gene essentiality

ABSTRACT: CRISPR-based gene knockouts assume that phenotypes directly reflect gene function. Here, we show that RNA exosome-dependent buffering frequently masks knockout phenotypes. Using combinatorial CRISPR screens, we identify RNA exosome-dependent genes whose loss-of-function phenotypes are revealed only when RNA surveillance is impaired. We find that the RNA exosome is required for both the initiation and maintenance of transcriptional adaptation, in which disruption of a trigger gene induces the compensatory upregulation of a buffering gene. Mechanistically, intronic Alu elements provide sequence homology between trigger-buffer gene pairs and regulate the formation of circular RNAs that suppress compensatory transcription. Disrupting splicing, deleting intronic Alu elements, or targeting the resulting circular RNAs reduces circular RNA abundance and enables transcriptional adaptation. Our results uncover a sequence-encoded mechanism in which intronic Alu-derived circular RNAs gate RNA exosome-dependent transcriptional adaptation to mask gene phenotypes, and suggest that gene essentiality is actively regulated by RNA exosome-mediated buffering, with broad implications for the interpretation of context-specific gene dependencies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE337450 | GEO | 2026/07/07

REPOSITORIES: GEO

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Project description:Transposable elements are viewed as ‘selfish genetic elements’, yet they contribute to gene regulation and genome evolution in diverse ways. More than half of the human genome consists of transposable elements. With over 1 million insertions, Alu elements belong to the short interspersed nuclear element (SINE) family of repetitive elements, and with over 1 million insertions they make up more than 10% of the human genome. Despite their abundance and the potential evolutionary advantages they confer, Alu elements can be mutagenic to the host as they can act as splice acceptors, inhibit translation of mRNAs and cause genomic instability. Alu elements are the main targets of the RNA-editing enzyme ADAR and the formation of Alu exons is suppressed by the nuclear ribonucleoprotein HNRNPC, but the broad effect of massive secondary structures formed by inverted-repeat Alu elements on RNA processing in the nucleus remains unknown. Here we show that DHX9, an abundant nuclear RNA helicase, binds specifically to inverted-repeat Alu elements that are transcribed as parts of genes. Loss of DHX9 leads to an increase in the number and amount of circular RNAs, translational repression of reporters containing inverted-repeat Alu elements, and transcriptional rewiring (the creation of mostly nonsensical novel connections between exons) of susceptible loci. Biochemical purifications of DHX9 identify the interferon-inducible isoform of ADAR (p150), but not the constitutively expressed ADAR isoform (p110), as an RNA-independent interaction partner. Co-depletion of ADAR and DHX9 augments the double-stranded RNA accumulation defects, leading to higher levels of circular RNA production, revealing a functional link between these two enzymes. Our work uncovers an evolutionarily conserved function of DHX9. We propose that it acts as a nuclear RNA resolvase that neutralizes the immediate threat posed by transposon insertions and allows these elements to evolve as tools for the post-transcriptional regulation of gene expression. This SuperSeries is composed of the SubSeries listed below.

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RNA exosome-dependent transcriptional adaptation masks gene essentiality

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