Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Integrator loss leads to dsRNA formation that triggers the Integrated Stress Response

ABSTRACT: Integrator (INT) is a metazoan-specific complex that targets promoter-proximally paused RNA polymerase II (RNAPII) for termination, preventing immature RNAPII from entering gene bodies and functionally attenuating transcription of stress-responsive genes. Mutations in INT subunits are associated with many human diseases, including cancer, ciliopathies and neurodevelopmental disorders, but how reduced INT activity contributes to disease is unknown. Here, we demonstrate that loss of INT-mediated termination in human cells triggers the integrated stress response (ISR). INT-depletion causes upregulation of short genes such as the ISR transcription factor ATF3. Further, immature RNAPII that escapes into genes upon INT-depletion is prone to premature termination, generating incomplete pre-mRNAs with retained introns. Retroelements within retained introns form double-stranded RNA (dsRNA) that is recognized by Protein Kinase R (PKR), which drives ATF4 activation and prolonged ISR. Critically, patient cells with INT mutations exhibit dsRNA accumulation and ISR activation, thereby implicating chronic ISR in diseases caused by INT-deficiency.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Kyle Swovick

LAB HEAD: Eric Wagner

PROVIDER: PXD060648 | Pride | 2026-01-08

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	Huang_A-1_23-269.raw	Raw
	Huang_A-2_23-269.raw	Raw
	Huang_A-3_23-269.raw	Raw
	Huang_A_plus-1_23-269.raw	Raw
	Huang_A_plus-2_23-269.raw	Raw

Items per page:

1 - 5 of 16

Similar Datasets

Disruption of the Integrator complex triggers the Integrated Stress Response through formation of double-stranded RNA [48h_INTS8_RNAseq]

Project description:Acute loss of INT induces transcription factors that initiate stress-responses like the Integrated Stress Response (ISR). Inefficient elongation upon INT loss enables termination in introns and dsRNA formation. dsRNA is recognized by PKR, which persistently activates the ISR in samples from patients with INT mutations

2025-04-16 | GSE283862 | GEO

Disruption of the Integrator complex triggers the Integrated Stress Response through formation of double-stranded RNA [RNAseq]

2025-04-16 | GSE267104 | GEO

Disruption of the Integrator complex triggers the Integrated Stress Response through formation of double-stranded RNA [RIPseq]

2025-04-16 | GSE267044 | GEO

Disruption of the Integrator complex triggers the Integrated Stress Response through formation of double-stranded RNA [PROseq]

2025-04-16 | GSE267042 | GEO

Disruption of the Integrator complex triggers the Integrated Stress Response through formation of double-stranded RNA [TTseq]

2025-04-16 | GSE267040 | GEO

CUT&Tag Overcomes Biases of ChIP and Establishes Chromatin Patterns for Repetitive Genomic Loci

Project description:Determining the genomic localization of chromatin features is an essential aspect of investigating gene expression control, and ChIP-Seq has long been the gold standard technique for interrogating chromatin landscapes. Recently, the development of alternative methods, such as CUT&Tag, have provided researchers with alternative strategies that eliminate the need for chromatin purification, and allow for in situ investigation of histone modifications and chromatin bound factors. Mindful of technical differences, we set out to investigate whether distinct chromatin modifications were equally compatible with these different chromatin interrogation techniques. We found that ChIP-Seq and CUT&Tag performed similarly for modifications known to reside at gene regulatory regions, such as promoters and enhancers, but major differences were observed when we assessed enrichment over heterochromatin-associated loci. Unlike ChIP-Seq, CUT&Tag detects robust levels of H3K9me3 at a substantial number of repetitive elements, with especially high sensitivity over evolutionarily young retrotransposons. IAPEz-int elements for example, exhibited underrepresentation in mouse ChIP-Seq datasets but strong enrichment using CUT&Tag. Additionally, we identified several euchromatin-associated proteins that co-purify with repetitive loci and are similarly depleted when applying ChIP-based methods. This study reveals that our current knowledge of chromatin states across the heterochromatin portions of the mammalian genome is extensively incomplete, largely due to36 limitations of ChIP-Seq. We also demonstrate that newer in situ chromatin fragmentation-based techniques, such as CUT&Tag and CUT&RUN, are more suitable for studying chromatin modifications over repetitive elements and retrotransposons.

2025-08-26 | PXD067760 | Pride

Integrator is a genome-wide attenuator of non-productive transcription

Project description:Termination of RNA polymerase II (RNAPII) transcription in metazoans relies largely on the Cleavage and Polyadenylation (CPA) and Integrator (INT) complexes originally found to act at the ends of protein-coding and snRNA genes, respectively. Here we monitor CPA- and INT-dependent termination activities genome-wide, including at thousands of previously unannotated transcription units (TUs), producing unstable RNA. We verify the global activity of CPA, occurring at pA sites indiscriminately of their positioning relative to the TU promoter. We also identify a global activity of INT, which is, however, largely sequence-independent and restricted to a ~3 kb promoter-proximal region. Our analyses suggest two functions of genome-wide INT activity; it dampens transcriptional output from weak promoters and it provides quality-control of RNAPII complexes that are unfavorably configured for transcriptional elongation. We suggest that the function of INT in stable snRNA production is an exception from its general cellular role, the attenuation of non-productive transcription.

2021-01-03 | GSE151919 | GEO

The Sen1 Helicase Prevents Spurious Transcription by Controlling Genome-Wide Transcription Termination by RNAPII

Project description:RNA Polymerase II (RNAPII) termination for transcripts containing a polyadenylation signal (PAS) is thought to differ mechanistically from termination for PAS-independent RNAPII transcripts such as sn(o)RNAs. In a screen for factors required for PAS-dependent termination, we identified Sen1, a putative helicase known primarily for its role in PAS-independent termination. We show that Sen1 is required for termination on hundreds of protein-coding genes and suppresses cryptic transcription from nucleosome-free regions on a genomic scale. These effects often overlap with but are also often distinct from those caused by Nrd1 depletion, which also impacts termination of protein-coding and cryptic transcripts, including many genic antisense transcripts. Sen1 controls termination through its helicase activity and stimulates recruitment of factors previously implicated in both PAS-dependent (Rna14, Rat1) and PAS-independent (Nrd1) termination. Thus, RNAPII termination for both protein-coding genes and cryptic transcripts is dependent on multiple pathways. The 2 RNAPII datasets were produced in duplicates and the Sen1 and Nrd1 datasets in triplicates (all IP/Input).

2011-06-01 | E-GEOD-19015 | biostudies-arrayexpress

A combinatorial approach to uncover a novel Integrator subunit

Project description:RNA polymerase II (RNAPII) controls the expression of all protein coding genes and most noncoding loci in higher eukaryotes. The ultimate rate of transcription is regulated at the level of multiple checkpoints during the transcription cycle (initiation, pausing, termination). Calibrating the activity of RNAPII is fundamental to all cellular processes and requires an assortment of polymerase-associated factors that are recruited at sites of active transcription. The Integrator complex is one of the most elusive transcriptional regulators in metazoans, deemed to be recruited after initiation to help establish and modulate paused RNAPII. Recent structural, biochemical, and functional evidence suggest that Integrator is composed of 14 subunits that assemble and operate in a modular fashion. We employed proteomics and machine-learning structure prediction (AlphaFold2) approaches to identify a novel Integrator subunit, INTS15. We report that INTS15 assembles primarily with the INTS13/INTS14/INTS10 module and interfaces with the core of the Int-PP2A complex. Functional genomics analysis further reveals a role for INTS15 in modulating RNAPII pausing at a subset of genes in human cell lines. Our study shows that omics approaches combined with AlphaFold2-based predictions provide novel insights into the molecular architecture of large and flexible multiprotein complexes.

2023-07-20 | PXD039956 | Pride

Multi-omics and biochemical reconstitution reveal CDK7-dependent mechanisms controlling RNA polymerase II function at gene 5'- and 3'-ends

Project description:CDK7 regulates RNA polymerase II (RNAPII) initiation, elongation, and termination through incompletely understood mechanisms. Because contaminating kinases precluded CDK7 analysis with nuclear extracts, we completed biochemical assays with purified factors. Reconstitution of RNAPII transcription initiation showed CDK7 inhibition slowed and/or paused RNAPII promoterproximal transcription, which reduced re-initiation. These CDK7-regulatory functions were suppressing RNAPII activity at promoters, consistent with reduced initiation and/or re-initiation. Moreover, widespread 3'-end readthrough transcription was observed in CDK7-inhibited cells; mechanistically, this occurred through rapid nuclear depletion of RNAPII elongation and termination factors, including high-confidence CDK7 targets. Collectively, these results define how CDK7 governs RNAPII function at gene 5'-ends and 3'-ends, and reveal that nuclear abundance of elongation and termination factors is kinase-dependent. Because 3'-readthrough transcription is commonly induced during stress, our results further suggest regulated suppression of CDK7 activity may enable this RNAPII transcriptional response.

2025-05-08 | PXD063535 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data