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Related Experiment Video

Updated: Jun 28, 2025

A Rapid In Vivo Bioassay for Developmentally Active Enhancers
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Mutant FOXO1 controls an oncogenic network via enhancer accessibility.

Hillary M Layden1, Jacob D Ellis1, Monica L Bomber1

  • 1Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

Cell Genomics
|April 11, 2024
PubMed
Summary

This study reveals how mutated FOXO1 transcription factor drives diffuse large B cell lymphoma (DLBCL) by altering gene accessibility. Rapid degradation of mFOXO1 identified its direct targets, crucial for understanding DLBCL transcriptional dysregulation.

Keywords:
ATAC-seqDLBCLFOXO1PRO-seqchromatin remodelingdark zoneenhancertherapeutics

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Area of Science:

  • Molecular Biology
  • Genetics
  • Oncology

Background:

  • Transcriptional dysregulation is a key feature of diffuse large B cell lymphoma (DLBCL).
  • Mutations in transcriptional regulators are common in DLBCL, but understanding their direct effects is challenging.
  • Existing methodologies lack the temporal resolution to distinguish direct from indirect transcriptional control effects.

Purpose of the Study:

  • To develop and apply a chemical-genetic method for inducible degradation of the transcription factor FOXO1.
  • To elucidate the direct targets and mechanisms of mutated FOXO1 (mFOXO1) in DLBCL.
  • To investigate the role of FOXO1 in maintaining chromatin accessibility and regulating gene expression in DLBCL.

Main Methods:

  • Chemical-genetic engineering for inducible degradation of FOXO1.
  • Nascent transcript detection to monitor gene expression dynamics.
  • Chromatin accessibility assays to assess regulatory element activity.
  • Analysis of direct transcriptional targets of mFOXO1.

Main Results:

  • Identified direct targets of mFOXO1 using rapid degradation and nascent transcription analysis.
  • mFOXO1 maintains enhancer accessibility at oncogenes critical for DLBCL.
  • Degradation of mFOXO1 impaired RNA polymerase release at specific target genes.
  • Wild-type FOXO1 showed similar but weaker target regulation and could complement mFOXO1 degradation.

Conclusions:

  • The developed chemical-genetic approach effectively separates direct and indirect transcriptional effects.
  • mFOXO1 plays a critical role in maintaining oncogene expression through enhancer regulation in DLBCL.
  • Targeting FOXO1 function represents a potential therapeutic strategy for DLBCL.