Mutant FOXO1 controls an oncogenic network via enhancer accessibility.
Cell Genom
; 4(4): 100537, 2024 Apr 10.
Article
in En
| MEDLINE
| ID: mdl-38604128
ABSTRACT
Transcriptional dysregulation is a hallmark of diffuse large B cell lymphoma (DLBCL), as transcriptional regulators are frequently mutated. However, our mechanistic understanding of how normal transcriptional programs are co-opted in DLBCL has been hindered by a lack of methodologies that provide the temporal resolution required to separate direct and indirect effects on transcriptional control. We applied a chemical-genetic approach to engineer the inducible degradation of the transcription factor FOXO1, which is recurrently mutated (mFOXO1) in DLBCL. The combination of rapid degradation of mFOXO1, nascent transcript detection, and assessment of chromatin accessibility allowed us to identify the direct targets of mFOXO1. mFOXO1 was required to maintain accessibility at specific enhancers associated with multiple oncogenes, and mFOXO1 degradation impaired RNA polymerase pause-release at some targets. Wild-type FOXO1 appeared to weakly regulate many of the same targets as mFOXO1 and was able to complement the degradation of mFOXO1 in the context of AKT inhibition.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Regulatory Sequences, Nucleic Acid
/
Forkhead Box Protein O1
Limits:
Humans
Language:
En
Journal:
Cell Genom
Year:
2024
Document type:
Article
Affiliation country:
United States
Country of publication:
United States