The TRRAP transcription cofactor represses interferon-stimulated genes in colorectal cancer cells

Abstract
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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.

The following data sets were generated

(2021) The TRRAP transcription cofactor represses interferon-stimulated genes in colorectal cancer cells
NCBI Gene Expression Omnibus, GSE171454.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE171454
(2021) The TRRAP transcription cofactor represses interferon-stimulated genes in colorectal cancer cells
NCBI Gene Expression Omnibus, GSE192527.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE192527

The following previously published data sets were used

1. Cheon H
2. Stark GR
(2013) Genes induced by IFN-beta, IFN-gamma or unphosphoraylted STAT1 in human fibroblasts
NCBI Gene Expression Omnibus, GSE50954.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE50954
1. Farnham - University of Southern California
(2012) USC_ChipSeq_HCT-116_H3K27ac_UCDavis
NCBI Gene Expression Omnibus, GSM945853.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM945853
1. Stamatoyannopoulous - University of Washington
(2012) UW_ChipSeq_HCT-116_H3K4me3
NCBI Gene Expression Omnibus, GSM945304.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM945304

Article and author information

Author details

Dylane Detilleux

CRBM, University of Montpellier, CNRS, Montpellier, France

Competing interests
The authors declare that no competing interests exist.
Peggy Raynaud

CRBM, University of Montpellier, CNRS, Montpellier, France

For correspondence
peggy.raynaud@crbm.cnrs.fr

Competing interests
The authors declare that no competing interests exist.
Berengere Pradet-Balade

CRBM, University of Montpellier, CNRS, Montpellier, France

For correspondence
berengere.pradet-balade@crbm.cnrs.fr

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1720-3739
Dominique Helmlinger

CRBM, University of Montpellier, CNRS, Montpellier, France

For correspondence
dhelmlinger@crbm.cnrs.fr

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1501-0423

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

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.