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| Status |
Public on Mar 14, 2024 |
| Title |
Cell of origin epigenetic priming determines susceptibility to Tet2 oncogenic mutation [scATAC-seq] |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Hematopoietic stem cell mutations can result in clonal hematopoiesis (CHIP) but the clinical outcomes are heterogeneous. The nature of the founder mutation and secondary mutations likely drive emergent neoplastic disease. We investigated how the cell state where the TET2 mutation occurs affects susceptibility to that commonly occurring CH mutation. Here, we provide evidence that risk is written in the epigenome of the cell of origin. By characterizing cell states that underlie myeloid differentiation and linking this information to an inducible system to assess myeloid progenitor clones, we provide evidence that epigenetic markers of the cell where Tet2 mutation occurs stratifies clonal behaviors. Specifically, Sox4 fosters a global cell state of high sensitization towards Tet2 KO. Using GMP and primary HSC models, we show that Sox4 promotes cell dedifferentiation, alters cell metabolism and increases the in vivo clonal output of mutant cells. Our results validate the hypothesis that epigenetic features can predispose specific clones for dominance and explain why an identical mutation can result in different outcomes.
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| Overall design |
Bone marrow hematopoietic progenitor cells from inducible Tet2 mutant mice or matched controls were profiled using the BioRad SureCell single-cell ATAC-seq platform. Our dataset included populations spanning from HSC to mature myeloid effector cells (Lin- progenitors, CD11b+ cells), and sorted GMPs (Lin- cKit+ Sca1- CD34+ CD16/32+).
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| Contributor(s) |
Duarte F, Schiroli G, Kartha V |
| Citation(s) |
38773071 |
| |
| Submission date |
Mar 14, 2023 |
| Last update date |
Jun 06, 2024 |
| Contact name |
Fabiana Duarte |
| E-mail(s) |
fabiana_duarte@g.harvard.edu
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| Organization name |
Harvard University
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| Department |
HSCRB
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| Lab |
Buenrostro lab
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| Street address |
7 Divinity Avenue
|
| City |
Cambridge |
| State/province |
Massachusetts |
| ZIP/Postal code |
02138 |
| Country |
USA |
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| Platforms (1) |
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| Samples (16)
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| This SubSeries is part of SuperSeries: |
| GSE247970 |
Cell of origin epigenetic priming determines susceptibility to Tet2 oncogenic mutation |
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| Relations |
| BioProject |
PRJNA944632 |
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