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| Status |
Public on Mar 25, 2024 |
| Title |
Mutant FOXO1 Controls an Oncogenic Network via Enhancer Accessibility and RNA Polymerase Pause Release [ChIP-seq/CUT&RUN] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Transcriptional dysregulation is a hallmark of diffuse large B-cell lymphoma (DLBCL), as multiple transcriptional regulators are 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 in transcriptional control. Here, we applied a chemical-genetic approach to engineer the inducible degradation of the transcription factor FOXO1, which is recurrently mutated in DLBCL. The combination of rapid degradation of FOXO1, nascent transcript detection, and accessible chromatin allowed us to identify the direct targets of FOXO1. FOXO1 degradation impaired RNA polymerase pause-release at many target genes. Furthermore, FOXO1 was required to maintain accessibility at specific enhancers associated with target genes. Importantly, many direct targets of FOXO1 were oncogenes including several effectors of the PI3K pathway, which creates a dependency on AKT signaling.
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| Overall design |
ChIP-seq (H3K27ac, Abcam ab4729) or CUT&RUN (H3K4me3 Abcam ab12209) was performed in the OCI-LY1 cell line expressing endogenous FOXO1-FKBPF36V at specified time points after treatment with dTAG-47.
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| Contributor(s) |
Layden HM, Hiebert SW |
| Citation(s) |
38604128 |
| |
| Submission date |
Jan 28, 2024 |
| Last update date |
May 01, 2024 |
| Contact name |
Scott Hiebert |
| E-mail(s) |
hillary.layden@vanderbilt.edu
|
| Organization name |
Vanderbilt University
|
| Street address |
2220 Pierce Ave, Hiebert Lab PRB 512
|
| City |
Nashville |
| State/province |
Tennessee |
| ZIP/Postal code |
37232 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA1070316 |
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