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| Status |
Public on Mar 26, 2024 |
| Title |
ZEB1 controls a lineage-specific transcriptional program essential for melanoma cell state transitions [ChIP-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Cell plasticity sustains intra-tumor heterogeneity and treatment resistance in melanoma. Deciphering the transcriptional mechanisms governing reversible phenotypic transitions between proliferative/differentiated and invasive/stem-like states is required. Expression of the ZEB1 transcription factor is frequently activated in melanoma, where it fosters adaptive resistance to targeted therapies. Here, we performed a genome-wide characterization of ZEB1 transcriptional targets, by combining ChIP-sequencing and RNA-sequencing, upon phenotype switching in melanoma models. We identified and validated ZEB1 binding peaks in the promoter of key lineage-specific genes crucial for melanoma cell identity. Mechanistically, ZEB1 negatively regulates SOX10-MITF dependent proliferative/melanocytic programs and positively regulates AP-1 driven invasive and stem-like programs. Comparative analyses with breast carcinoma cells revealed lineage-specific ZEB1 binding, leading to the design of a more reliable melanoma-specific ZEB1 regulon. We then developed single-cell spatial multiplexed analyses to characterize melanoma cell states intra-tumoral heterogeneity in human melanoma samples. Combined with scRNA-Seq analyses, our findings confirmed increased ZEB1 expression in Neural-Crest-like cells and mesenchymal cells, underscoring its significance in vivo in both populations. Overall, our results define ZEB1 as a major transcriptional regulator of cell states transitions and provide a better understanding of lineage-specific transcriptional programs sustaining intra-tumor heterogeneity in melanoma.
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| Overall design |
ZEB1 ChIP-seq were performed on untreated and treated GLO cells and AS3 melanoma cells.
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| Contributor(s) |
Durand S, Tang Y, Pommier RM, Benboubker V, Grimont M, Boivin F, Barbollat L, Cumunel E, Dupeuble F, Eberhardt A, Plaschka M, Dalle S, Caramel J |
| Citation(s) |
38519642 |
| |
| Submission date |
Oct 31, 2023 |
| Last update date |
May 29, 2024 |
| Contact name |
Julie CARAMEL |
| E-mail(s) |
julie.caramel@lyon.unicancer.fr
|
| Phone |
+33426556705
|
| Organization name |
Cancer Research Center of Lyon
|
| Street address |
28 Rue Laennec
|
| City |
LYON |
| ZIP/Postal code |
69008 |
| Country |
France |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (8)
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| This SubSeries is part of SuperSeries: |
| GSE246673 |
ZEB1 controls a lineage-specific transcriptional program essential for melanoma cell state transitions |
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| Relations |
| BioProject |
PRJNA1034110 |
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