|
| Status |
Public on May 05, 2024 |
| Title |
A myeloid maturation program initiated by nucleotide depletion during S phase [ATAC-Seq] |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Certain cancers, such as acute myeloid leukemia (AML), are caused by malignant stem cells that fail maturation. We sought to mechanistically understand how metabolism might regulate cell fate decisions and to identify metabolic differentiation agents that might be leveraged therapeutically. We find that nucleotide – purine, pyrimidine, and deoxynucleotide – depletion leads to AML differentiation by way of replication stress. Modulation of nucleotide pools leads to transcriptional reprogramming, epigenetic remodeling, and initiation of differentiation which is dependent on the myeloid regulating transcription-factor PU.1. By single-cell RNA sequencing and microscopy, we find that reprogramming downstream of nucleotide depletion occurs as cells undergo replication stress and that the cell fate decision is initiated prior to completion of the cell cycle. Together, these findings suggest that nucleotide metabolism is a critical determinant of hematopoietic progenitor cell fate, clarify the coordination of the fate decision with the cell cycle, and expand upon the class of inhibitors that can be developed or repurposed as novel differentiation therapy.
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| Overall design |
Cell lines were treated with vehicle or drug for the indicated times and ATACseq was performed.
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| Contributor(s) |
Do BT, Hsu PP, Vermeulen SY, Sykes DB, Vander Heiden MG |
| Citation(s) |
38823395 |
| |
| Submission date |
Apr 19, 2021 |
| Last update date |
Aug 04, 2024 |
| Contact name |
Brian Do |
| E-mail(s) |
bdo311@gmail.com
|
| Organization name |
MIT
|
| Department |
Biology
|
| Lab |
Vander Heiden
|
| Street address |
500 Main St
|
| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02139 |
| Country |
USA |
| |
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| Platforms (3) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
|
| Samples (48)
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| This SubSeries is part of SuperSeries: |
| GSE172335 |
Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress |
|
| Relations |
| BioProject |
PRJNA722864 |
| SRA |
SRP315288 |
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