The TRRAP transcription cofactor represses interferon-stimulated genes in colorectal cancer cells
- University of Montpellier, CNRS, France
Abstract
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 PIKK family 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 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 (CRC). 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.
Data availability
The raw sequencing data reported in this publication have been deposited in NCBI Gene Expression Omnibus and are accessible through GEO Series accession number GSE171454 and GSE192527.
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The TRRAP transcription cofactor represses interferon-stimulated genes in colorectal cancer cellsNCBI Gene Expression Omnibus, GSE171454.
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The TRRAP transcription cofactor represses interferon-stimulated genes in colorectal cancer cellsNCBI Gene Expression Omnibus, GSE192527.
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Genes induced by IFN-beta, IFN-gamma or unphosphoraylted STAT1 in human fibroblastsNCBI Gene Expression Omnibus, GSE50954.
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USC_ChipSeq_HCT-116_H3K27ac_UCDavisNCBI Gene Expression Omnibus, GSM945853.
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UW_ChipSeq_HCT-116_H3K4me3NCBI Gene Expression Omnibus, GSM945304.
Article and author information
Author details
Berengere Pradet-Balade
Dominique Helmlinger
Funding
Fondation ARC pour la Recherche sur le Cancer (PJA-20181208277)
- Dominique Helmlinger
Institut National Du Cancer (PLBIO 2016-161)
- Berengere Pradet-Balade
- Dominique Helmlinger
Ligue Nationale Contre le Cancer (Graduate Student Fellowship)
- Dylane Detilleux
Ligue Nationale Contre le Cancer (Comité Hérault)
- Peggy Raynaud
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Detilleux et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The TRRAP transcription cofactor represses interferon-stimulated genes in colorectal cancer cells
eLife 11:e69705.
https://doi.org/10.7554/eLife.69705
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