The TRRAP transcription cofactor represses interferon-stimulated genes in colorectal cancer cells II
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ABSTRACT:
PROVIDER: PRJNA791840 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR17319782_1.fastq.gz | Fastqsanger.gz | |||
| SRR17319782_2.fastq.gz | Fastqsanger.gz | |||
| SRR17319783_1.fastq.gz | Fastqsanger.gz | |||
| SRR17319783_2.fastq.gz | Fastqsanger.gz | |||
| SRR17319784_1.fastq.gz | Fastqsanger.gz |
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Project description:The TRRAP transcription cofactor represses interferon-stimulated genes in colorectal cancer cells
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Project description:Transcription is essential for cells to respond to signaling cues and involves factors with multiple distinct activities. One such factor, TRRAP, functions as part of two large complexes, SAGA and TIP60, which have essential roles during transcription activation. Structurally, TRRAP belongs to the family PIKKs but is the only member classified as a pseudokinase. Recent studies established that a dedicated HSP90 co-chaperone, the TTT complex, is essential for PIKK maturation and activity. Here we used endogenous auxin-inducible degron alleles to show that the TTT subunit TELO2 promotes TRRAP assembly into SAGA and TIP60 in human colorectal cancer cells (CRC). Transcriptomic analysis revealed that TELO2 contribute to TRRAP regulatory roles in CRC cells, most notably of MYC target genes. Surprisingly, TELO2 and TRRAP depletion also induced the expression of type I interferon genes. Using a combination of nascent RNA, antibody-targeted chromatin profiling (CUT&RUN) and kinetic analyses, we show that TRRAP directly represses the expression of IRF9, which is a master regulator of interferon stimulated genes. We have therefore uncovered a new, unexpected transcriptional repressor role for TRRAP, suggesting a previously unidentified mechanism by which TRRAP may contribute to tumorigenesis.
2022-01-07 | GSE171454 | GEO
Project description:Transcription is essential for cells to respond to signaling cues and involves factors with multiple distinct activities. One such factor, TRRAP, functions as part of two large complexes, SAGA and TIP60, which have essential roles during transcription activation. Structurally, TRRAP belongs to the family PIKKs but is the only member classified as a pseudokinase. Recent studies established that a dedicated HSP90 co-chaperone, the TTT complex, is essential for PIKK maturation and activity. Here we used endogenous auxin-inducible degron alleles to show that the TTT subunit TELO2 promotes TRRAP assembly into SAGA and TIP60 in human colorectal cancer cells (CRC). Transcriptomic analysis revealed that TELO2 contribute to TRRAP regulatory roles in CRC cells, most notably of MYC target genes. Surprisingly, TELO2 and TRRAP depletion also induced the expression of type I interferon genes. Using a combination of nascent RNA, antibody-targeted chromatin profiling (CUT&RUN) and kinetic analyses, we show that TRRAP directly represses the expression of IRF9, which is a master regulator of interferon stimulated genes. We have therefore uncovered a new, unexpected transcriptional repressor role for TRRAP, suggesting a previously unidentified mechanism by which TRRAP may contribute to tumorigenesis.
2022-01-07 | GSE192527 | GEO
Project description:Transcription is essential for cells to respond to signaling cues and involves factors with multiple distinct activities. One such factor, TRRAP, functions as part of two large complexes, SAGA and TIP60, which have crucial roles during transcription activation. Structurally, TRRAP belongs to the phosphoinositide 3 kinase-related kinases (PIKK) family but is the only member classified as a pseudokinase. Recent studies established that a dedicated HSP90 co-chaperone, the triple T (TTT) complex, is essential for PIKK stabilization and activity. Here, using endogenous auxin-inducible degron alleles, we show that the TTT subunit TELO2 promotes TRRAP assembly into SAGA and TIP60 in human colorectal cancer cells (CRCs). Transcriptomic analysis revealed that TELO2 contributes to TRRAP regulatory roles in CRC cells, most notably of MYC target genes. Surprisingly, TELO2 and TRRAP depletion also induced the expression of type I interferon genes. Using a combination of nascent RNA, antibody-targeted chromatin profiling (CUT&RUN), ChIP, and kinetic analyses, we propose a model by which TRRAP directly represses the transcription of IRF9, which encodes a master regulator of interferon-stimulated genes. We have therefore uncovered an unexpected transcriptional repressor role for TRRAP, which we propose contributes to its tumorigenic activity.
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Project description:Brain homeostasis is regulated by the viability and functionality of neurons. HAT (histone acetyltransferase) and HDAC (histone deacetylase) inhibitors have been applied to treat neurological deficits in humans; yet, the epigenetic regulation in neurodegeneration remains elusive. Mutations of HAT cofactor TRRAP (Transformation/translation domain-associated protein) cause human neuropathies, including psychosis, intellectual disability, autism and epilepsy, with unknown mechanism. Here we show that Trrap deletion in Purkinje neurons results in neurodegeneration of old mice. Integrated transcriptomics, epigenomics and proteomics reveal that TRRAP via SP1 conducts a conserved transcriptomic program. TRRAP is required for SP1 binding at the promoter proximity of target genes, especially microtubule dynamics. The ectopic expression of Stathmin3/4 ameliorates defects of TRRAP-deficient neurons, indicating that the microtubule dynamics is particularly vulnerable to the action of SP1 activity. This study unravels a network linking three well-known, but up-to-date unconnected, signaling pathways, namely TRRAP, HAT and SP1 with microtubule dynamics, in neuroprotection.
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Project description:HAT cofactor TRRAP modulates microtubule dynamics via SP1 signaling to prevent neurodegeneration
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Project description:Epigenetic control of neural stem/progenitor cell fate is fundamental to achieve a fully brain architecture. Two intrinsic programs regulate neurogenesis, one by epigenetic-mediated gene transcription and another by cell cycle control. Whether and how these two are coordinated to determine temporally and spatially neural development remains unknown. Here we show that deletion of Trrap (Transcription translation associated protein), an essential cofactor for HAT (histone acetyltransferase), leads to severe brain atrophy due to a combination of cell death and a blockade of neuron production. Specifically, Trrap deletion forces differentiation of apical progenitor (AP) fate into basal progenitors (BP) and neurons thereby limiting the total neurogenic production. Despite TrrapM-bM-^@M-^Ys general role in transcriptional regulation, a genome-wide transcriptome analysis of neuroprogenitors identified the cell cycle regulators that are specifically affected by Trrap deletion. Furthermore, E2F-dependent recruitment of HAT and transcription factors to the promoter of cell cycle regulators is impaired in Trrap-deleted neuroprogenitors. Consistent with these molecular changes, Trrap deletion lengthens particularly G1 and S phases in APs in vivo. Therefore, our study reveals an essential and a distinct function of Trrap-HAT in regulation of cell cycle progression that is required for proper determination of neuroprogenitor fate. Determine gene transcriptions by comparing Trrap-deleted and wild type samples
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Project description:PRDM16 is a strong activator of brown fat-specific genes, while also a repressor of white fat and muscle-specific genes. We asked what other pathways are regulated by PRDM16 in adipocytes that may be critical for brown and/or beige adipogenesis. Using microarray, we found PRDM16 also represses type I Interferon-stimulated genes (ISGs) in adipocytes.
2017-04-10 | GSE86016 | GEO
Project description:Epigenetic control of neural stem/progenitor cell fate is fundamental to achieve a fully brain architecture. Two intrinsic programs regulate neurogenesis, one by epigenetic-mediated gene transcription and another by cell cycle control. Whether and how these two are coordinated to determine temporally and spatially neural development remains unknown. Here we show that deletion of Trrap (Transcription translation associated protein), an essential cofactor for HAT (histone acetyltransferase), leads to severe brain atrophy due to a combination of cell death and a blockade of neuron production. Specifically, Trrap deletion forces differentiation of apical progenitor (AP) fate into basal progenitors (BP) and neurons thereby limiting the total neurogenic production. Despite Trrap’s general role in transcriptional regulation, a genome-wide transcriptome analysis of neuroprogenitors identified the cell cycle regulators that are specifically affected by Trrap deletion. Furthermore, E2F-dependent recruitment of HAT and transcription factors to the promoter of cell cycle regulators is impaired in Trrap-deleted neuroprogenitors. Consistent with these molecular changes, Trrap deletion lengthens particularly G1 and S phases in APs in vivo. Therefore, our study reveals an essential and a distinct function of Trrap-HAT in regulation of cell cycle progression that is required for proper determination of neuroprogenitor fate.
2014-05-01 | GSE43650 | GEO
Project description:STAT1 plays a cental role in the induction of interferon-stimulated genes, but interferon alpha can activate a STAT1-independent pathway that leads to gene expression. We performed microarray analysis to examine whether like interferon alpha, interferon lambda, a newly discovered interferon, can induce the expression of interferon-stimulated genes in the absence of STAT1.
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