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

Dylane Detilleux,Peggy Raynaud,Berengere Pradet-Balade,Dominique Helmlinger

doi:10.7554/elife.69705

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 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.

Highlights

Transcriptional regulation is crucial for cells to adapt to external changes, for example during development or to maintain homeostasis
A conditional approach was dictated by the observations that both TELO2 and TRRAP are essential for early embryonic development and cell proliferation [22, 32]
Using an adjusted P-value threshold of 0.05, we found that nearly one third of the 97 interferon-stimulated genes (ISGs) (28/97) from the IFN response hallmark is differentially expressed in absence of TELO2 and TRRAP (Figure 2C, right panels)

Summary

Introduction

Transcriptional regulation is crucial for cells to adapt to external changes, for example during development or to maintain homeostasis. A critical step in gene expression is the initiation of transcription, which is controlled by both cis- and trans-regulatory mechanisms. These include the coordinated activities of large, multimeric complexes that modify histones or remodel nucleosomes at promoters. These complexes often function as co-activators, bridging DNA-bound transcription factors to the general transcription machinery. Similar to the general transcription factor TFIID, with which it shares four core TAF subunits in humans, SAGA delivers TBP to specific promoters, stimulating pre-initiation complex (PIC) assembly. TIP60 carries HAT activity and, through the EP400 subunit, catalyzes deposition of the H2A.Z variant. TIP60 acetylates histone H4 and H2A, as well as the histone variant H2A.Z

Methods

Results

Conclusion