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| Status |
Public on Sep 26, 2024 |
| Title |
TGF-β and RAS jointly unmask primed enhancers to drive metastasis (Mnase-Seq) |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Epithelial-to-mesenchymal transitions (EMTs) and extracellular matrix (ECM) remodeling are distinct yet important processes during carcinoma invasion and metastasis. TGF-β and RAS, signaling through SMAD and RAS-responsive element-binding protein 1 (RREB1), jointly trigger expression of EMT and fibrogenic factors as two discrete arms of a common transcriptional response in carcinoma cells. Here we demonstrate that both arms form a program for lung adenocarcinoma pulmonary metastasis and identify chromatin determinants tying the expression of the constituent genes to TGF-β and RAS dual inputs. RREB1 binds near H4K16ac histone marks and histone H2A.Z-loaded nucleosomes at enhancers in the fibrogenic genes IL11, PDGFB, and HAS2 and the EMT transcription factor SNAI1, priming these enhancers for activation by a SMAD4-INO80 nucleosome remodeling complex in response to TGF-β. These regulatory properties set the fibrogenic EMT program apart from RAS-independent TGF-β gene responses and illuminate the operation and vulnerabilities of a transcriptional program that promotes metastatic outgrowth.
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| Overall design |
Nucleosome occupancy profiling by high throughput sequencing of 393T3 cells, a cell line derived from a lung tumor from a KrasG12D;p53-/- (KP) genetically engineered mouse model, treated with SB505124 or TGF-β for 1.5 h
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| Contributor(s) |
Lee J, Koche RP, Massagué J |
| Citation missing |
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| |
| Submission date |
Feb 16, 2024 |
| Last update date |
Sep 27, 2024 |
| Contact name |
Jun Ho Lee |
| E-mail(s) |
jhlee90710@gmail.com
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| Organization name |
MSKCC
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| Street address |
417 E 68th St
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| City |
New York |
| ZIP/Postal code |
10065 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (2) |
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| This SubSeries is part of SuperSeries: |
| GSE256020 |
TGF-β and RAS jointly unmask primed enhancers to drive metastasis |
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| Relations |
| BioProject |
PRJNA1077393 |
