Targeted enhancer activation by a subunit of the integrator complex
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA416461 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6237710.fastq.gz | Fastqsanger.gz | |||
| SRR6237720.fastq.gz | Fastqsanger.gz | |||
| SRR6237730.fastq.gz | Fastqsanger.gz | |||
| SRR6237711.fastq.gz | Fastqsanger.gz | |||
| SRR6237721.fastq.gz | Fastqsanger.gz |
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Project description:The control of cell fate is an epigenetic process initiated by transcription factors (TFs) that recognize DNA motifs and recruit activator complexes and transcriptional machineries to chromatin. Lineage specificity is thought to be provided solely by TF-motif pairing, while the recruited activators are passive. Here, we show that INTS13, a subunit of the Integrator complex, operates as monocytic/macrophagic differentiation factor. Integrator is a general activator of transcription at coding genes and is required for eRNA maturation. Here, we show that INTS13 functions as an independent sub-module and targets enhancers through Early Growth Response (EGR1/2) TFs and their co-factor NAB2. INTS13 binds poised monocytic enhancers eliciting chromatin looping and activation. Independent depletion of INTS13, EGR1, or NAB2 impairs monocytic differentiation of cell lines and primary human progenitors. Our data demonstrate that Integrator is not functionally homogeneous and has TF-specific regulatory potential, revealing a new enhancer regulatory axis that controls myeloid differentiation.
| S-EPMC6051407 | biostudies-literature
Project description:We investigated the genomic occupancy of INTS13 during monocytic differentiation, in in vitro differentiated monocytes and a leukemia-derived cell line. We produced genome wide data for steady state RNA (total RNA-seq) and chromatin-associated RNA (chromatin RNA-seq). Further, we used ChIP-seq to examine genome-wide distribution of INTS13, INTS11, EGR1 and NAB2, as well as the changes in occupancy of RNAPII, H3K4me1 and H3K27ac.
2018-03-01 | GSE106359 | GEO
Project description:Genome wide association studies of human lung function have identified a signal on 4q24 but the mechanistic basis for this signal is unclear. This region contains the Integrator Complex subunit 12 gene (INTS12) and nearby polymorphisms associated with lung function correlate with INTS12 expression. We aimed to define INTS12 function in human bronchial epithelial cells. RNAseq pathway analyses of INTS12 depleted cells revealed robust downregulation of several protein synthesis related pathways, including the aminoacyl tRNA synthetases and PERK regulated gene expression. Indeed, INTS12 knockdown using mRNA silencing repressed cellular translation and proliferation. ChIPseq gene-centric analyses revealed INTS12 binding to be near transcriptional start sites. The binding was found to be enriched for differentially expressed loci identifying the genes it regulates, a finding previously unknown for this particular member of Integrator complex. These findings contribute to the biology behind genetic association
2017-06-12 | GSE80386 | GEO
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.
2020-07-21 | GSE125534 | GEO
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.
2020-07-21 | GSE125535 | GEO
Project description:The eye and brain are composed of elaborately organized tissues, development of which is supported by spatiotemporally precise expression of a number of transcription factors and developmental regulators. Here we report the molecular and genetic characterization of Integrator complex subunit 15 (INTS15). INTS15 was identified in search for the causative gene(s) for an autosomal-dominant eye disease with variable individual manifestation found in a large pedigree. While homozygous INTS15 knockout mice are embryonic lethal, mutant mice lacking a small C-terminal region of INTS15 show ocular malformations similar to the human patients. INTS15 is highly expressed in the eye and brain during embryogenesis and stably interacts with the Integrator complex to support snRNA 3′ end processing. Its knockdown resulted in missplicing of a large number of genes, probably as a secondary consequence, and substantially affected genes associated with eye and brain development. Moreover, studies using human iPS-derived neural progenitor cells showed that INTS15 is critical for axonal outgrowth in retinal ganglion cells. This study suggests a new link between general transcription machinery and a highly specific hereditary disease.
2023-03-08 | GSE186331 | GEO
Project description:Integrator complex subunit 15 controls mRNA splicing and is critical for eye development
| PRJNA773409 | ENA
Project description:Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal
| PRJNA1161690 | ENA
Project description:Lineage-specific transcription factors (TFs) operate as master orchestrators of developmental processes by activating select cis-regulatory enhancers and proximal promoters. Direct DNA binding of TFs ultimately drives context-specific recruitment of the basal transcriptional machinery that comprises RNA Polymerase II (RNAPII) and a host of polymerase-associated multiprotein complexes, including the metazoan-specific Integrator complex. Integrator is primarily known to modulate RNAPII processivity and to surveil RNA integrity across coding genes. Here we show an enhancer module of Integrator that directs cell fate specification by promoting epigenetic changes and TF binding at neural enhancers. Depletion of Integrator’s INTS10 upends neural traits and derails cells towards mesenchymal identity. Commissioning of neural enhancers relies on Integrator’s enhancer module, which stabilizes SOX2 binding at chromatin upon exit from pluripotency. We propose Integrator as a functional bridge between enhancers and promoters and a main driver of early development, providing new insight into a growing family of neurodevelopmental syndromes.
2024-08-15 | PXD054928 | Pride
Project description: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, assembling, and operating in a modular fashion. We employed proteomics and machine-learning (alphafold2) approaches to discover a novel Integrator subunit, INTS15. We report that INTS15 assembles primarily with the INTS10-INTS13-INTS14 module and interfaces with the Int-PP2A phosphatase module. Functional genomics analysis further reveals a role for INTS15 in modulating RNAPII pausing at a subset of genes in human cell lines.
2023-01-25 | GSE204905 | GEO