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Adulthood depletion of Integrator extends lifespan and healthspan via defective pre-mRNA processing [ChIP-seq]

ABSTRACT: Identifying strategies to mitigate age-related physiological decline remains a central challenge. Transcriptional regulation is essential to organismal healthspan and a frequent therapeutic target in ageing research. The Integrator complex is a highly conserved regulator of transcriptional quality control and RNA processing, yet its role in ageing within an intact organism remains unknown. Using adult-specific RNAi in Caenorhabditis elegans, we find that depletion of most Integrator subunits extends lifespan and healthspan. Mechanistically, loss of the catalytic subunit INTS11 disrupts 3′ end formation of small nuclear and spliced-leader RNAs, impairing trans-splicing and promoting outron retention on a subset of transcripts enriched for spliceosomal, nucleocytoplasmic import and mitochondrial functions. These RNA-processing defects engage endogenous siRNA pathways, which are required for the longevity and healthspan benefits of INTS11 depletion, consistent with a role in buffering the cytoplasmic burden of misprocessed splicing and import factors. In parallel, outron retention compromises nuclear-encoded mitochondrial gene expression and induces a hormetic decline in mitochondrial function. Together, our findings identify Integrator as an upstream regulator of a coupled RNA-processing–small RNA–mitochondrial axis that shapes the pace of ageing.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE325597 | GEO | 2026/04/27

REPOSITORIES: GEO

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Adulthood depletion of Integrator extends lifespan and healthspan via defective pre-mRNA processing [smallRNA-seq]

Project description:Identifying strategies to mitigate age-related physiological decline remains a central challenge. Transcriptional regulation is essential to organismal healthspan and a frequent therapeutic target in ageing research. The Integrator complex is a highly conserved regulator of transcriptional quality control and RNA processing, yet its role in ageing within an intact organism remains unknown. Using adult-specific RNAi in Caenorhabditis elegans, we find that depletion of most Integrator subunits extends lifespan and healthspan. Mechanistically, loss of the catalytic subunit INTS11 disrupts 3′ end formation of small nuclear and spliced-leader RNAs, impairing trans-splicing and promoting outron retention on a subset of transcripts enriched for spliceosomal, nucleocytoplasmic import and mitochondrial functions. These RNA-processing defects engage endogenous siRNA pathways, which are required for the longevity and healthspan benefits of INTS11 depletion, consistent with a role in buffering the cytoplasmic burden of misprocessed splicing and import factors. In parallel, outron retention compromises nuclear-encoded mitochondrial gene expression and induces a hormetic decline in mitochondrial function. Together, our findings identify Integrator as an upstream regulator of a coupled RNA-processing–small RNA–mitochondrial axis that shapes the pace of ageing.

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Project description:Complexes containing INTS3 and either NABP1 or NABP2 were initially characterized in DNA damage responses, but their biochemical function remained unknown. Using affinity purifications and HIV Integration Targeting-Sequencing (HIT-Seq), we find that these complexes are part of the Integrator complex, which binds RNA Polymerase II and regulates specific target genes. Integrator cleaves snRNAs as part of their processing to their mature form in a mechanism that is intimately coupled with transcription termination. However, HIT-Seq reveals that Integrator also binds to the 3’ end of replication-dependent histones and promoter proximal regions of genes with polyadenylated transcripts. Depletion of Integrator subunits results in transcription termination failure, disrupting histone mRNA processing, and leading to polyadenylation of snRNAs and histone mRNAs. Furthermore, promoter proximal binding of Integrator negatively regulates expression of genes whose transcripts are normally polyadenylated. Integrator recruitment to all three gene classes is DSIF-dependent, suggesting that Integrator functions as a termination complex at DSIF-dependent RNA Polymerase II pause sites. HITseq was used to interrogate chromatin binding sites of of proteins in the complex (including INIP, INTS3, INTS9, INTS11, NABP1, NABP2, NELFA, NELFB, NELFCD, NELFE, SPT5). These proteins were fused to LEDGF-IBD and expressed in mouse LEDGF-/-MEF cells. The fusion proteins then target HIV integration to the chromatin binding sites. The HIV integration sites were identified using linker-mediated PCR and highthroughput sequencing and serve as surrogate for chromatin binding sites. Mapping was done using mouse genome mm9.

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The Integrator complex cleaves many nascent mRNAs to attenuate transcription

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Project description:Pausing of RNA polymerase II (RNAPII) in early elongation is critical for gene regulation. Paused RNAPII can be released into productive elongation by the kinase P-TEFb or targeted for premature termination by the Integrator complex. Integrator comprises endonuclease and phosphatase activities, driving termination through cleavage of nascent RNA and removal of stimulatory phosphorylation. To probe the direct consequences of Integrator activity, we generated a degron system to rapidly deplete the Integrator endonuclease INTS11. Degradation of INTS11 elicits a nearly universal increase in RNAPII escape from promoter regions. However, these RNAPII complexes fail to achieve optimal elongation rates and reveal continued Integrator phosphatase activity. Short transcripts are thus selectively upregulated by INTS11 loss, including many non-coding RNAs, transcription factors and signaling regulators. Together, our data indicate a common function for INTS11 at all RNAPII loci, with differential effects on particular genes, pathways or RNA biotypes reflecting transcript lengths rather than Integrator specificity.

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