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Integrator complex bridges TFIID and RNA polymerase II to maintain pluripotency during development (ChIP-Seq)

ABSTRACT: The mechanisms by which the expression of pluripotency and Polycomb networks are harmonized to allow the transition from the pluripotency to a differentiated state has not been fully elucidated. Integrator complex regulates transcription pause release and RNA processing in metazoans. Here, we show that acute depletion of INTS11 in mouse embryonic stem cells or its conditional deletion in mouse results in loss of stemness and block of early embryonic development, respectively. We show that Integrator plays a role in stemness and cellular differentiation by bridging the association of RNA polymerase II (RNAPII) and basal transcription factor (TFIID). While the catalytic endonuclease activity is required to enhance cellular reprogramming, depletion of INTS11 diminish RNAPII recruitment to promoters and super-enhancers of pluripotency and Polycomb genes leading to their repression. We place Integrator at pre-initiation complex formation linking the pluripotency and Polycomb pathways to ensure orderly cellular differentiation during development.

ORGANISM(S): Mus musculus

PROVIDER: GSE268146 | GEO | 2025/08/08

REPOSITORIES: GEO

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Integrator complex bridges TFIID and RNA polymerase II to maintain pluripotency during development (PRO-Seq)

Project description:The mechanisms by which the expression of pluripotency and Polycomb networks are harmonized to allow the transition from the pluripotency to a differentiated state has not been fully elucidated. Integrator complex regulates transcription pause release and RNA processing in metazoans. Here, we show that acute depletion of INTS11 in mouse embryonic stem cells or its conditional deletion in mouse results in loss of stemness and block of early embryonic development, respectively. We show that Integrator plays a role in stemness and cellular differentiation by bridging the association of RNA polymerase II (RNAPII) and basal transcription factor (TFIID). While the catalytic endonuclease activity is required to enhance cellular reprogramming, depletion of INTS11 diminish RNAPII recruitment to promoters and super-enhancers of pluripotency and Polycomb genes leading to their repression. We place Integrator at pre-initiation complex formation linking the pluripotency and Polycomb pathways to ensure orderly cellular differentiation during development.

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Integrator endonuclease drives promoter-proximal termination at all RNAPII transcribed loci (RNA-Seq 2)

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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The Human Integrator Complex Facilitates Transcriptional Elongation by Endonucleolytic Cleavage of Nascent Transcripts

Project description:Transcription by RNA polymerase II (RNAPII) is pervasive in the human genome. However, the mechanisms controlling transcription at promoters and enhancers remain enigmatic. Here, we demonstrate that Integrator subunit 11 (INTS11), the catalytic subunit of the Integrator complex, regulates transcription at these loci through its endonuclease activity. Promoters of genes require INTS11 to cleave nascent transcripts associated with paused RNAPII and induce their premature termination in the proximity of the +1 nucleosome. The turnover of RNAPII permits the subsequent recruitment of an elongation-competent RNAPII complex, leading to productive elongation. In contrast, enhancers require INTS11 catalysis not to evict paused RNAPII but rather to terminate enhancer RNA transcription beyond the +1 nucleosome. These findings are supported by the differential occupancy of negative elongation factor (NELF), SPT5, and tyrosine-1-phosphorylated RNAPII. This study elucidates the role of Integrator in mediating transcriptional elongation at human promoters through the endonucleolytic cleavage of nascent transcripts and the dynamic turnover of RNAPII.

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