Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA722984 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14270700_1.fastq.gz | Fastqsanger.gz | |||
| SRR14270700_2.fastq.gz | Fastqsanger.gz | |||
| SRR14270701_1.fastq.gz | Fastqsanger.gz | |||
| SRR14270701_2.fastq.gz | Fastqsanger.gz | |||
| SRR14270702_1.fastq.gz | Fastqsanger.gz |
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Project description:This SuperSeries is composed of the SubSeries listed below.
2024-05-04 | GSE172335 | GEO
Project description: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.
2024-05-05 | GSE262392 | GEO
Project description: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.
2024-05-05 | GSE172300 | GEO
Project description: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.
2024-05-05 | GSE172299 | GEO
Project description: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.
2024-05-05 | GSE211065 | GEO
Project description: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.
2024-05-04 | GSE172296 | GEO
Project description: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.
2024-05-05 | GSE172333 | GEO
Project description:The sources of genome instability, a hallmark of cancer, remain incompletely understood. One potential source is DNA re-replication, which arises when the mechanisms that prevent re-initiation of replication origins within a single cell cycle are compromised. Using the budding yeast Saccharomyces cerevisiae, we previously showed that DNA re-replication is extremely potent at inducing gross chromosomal alterations and that this arises in part because of the susceptibility of re-replication forks to break. Here, we examine the ability of DNA re-replication to induce nucleotide level mutations. During normal replication these mutations are restricted by three overlapping error avoidance mechanisms: the nucleotide selectivity of replicative polymerases, their proofreading activity, and mismatch repair. Using lys2InsEA14, a frameshift reporter that is poorly proofread, we show that re-replication induces up to a 30x higher rate of frameshift mutations and that this mutagenesis is due to passage of the re-replication fork, not secondary to re-replication fork breakage. Re-replication can also induce comparable rates of frameshift and base substitution mutations in a more general mutagenesis reporter CAN1, when the proofreading activity of DNA polymerase ε is inactivated. Finally, we show that the induction of lys2InsEA14 frameshift mutations by re-replication is dependent on mismatch repair. These results suggest that the mismatch repair associated with re-replication is attenuated, although at most sequences DNA polymerase proofreading provides enough error correction to mitigate the mutagenic consequences. Thus, re-replication can facilitate nucleotide level mutagenesis in addition to inducing gross chromosomal alterations, broadening its potential role in genome instability.
2018-12-27 | GSE124382 | GEO
Project description:A myeloid maturation program initiated by nucleotide depletion during S phase [ery_scrnaseq]
| PRJNA1091642 | ENA
Project description:Helicobacter pylori (H.pylori) infection is a significant risk factor for gastric cancer (GC) development. A growing body of evidence suggests a causal link between infection with H.pylori and increased DNA breakage in the host cells. While several mechanisms have been proposed for this damage, their relative impact on the overall bacterial genotoxicity is unknown. Moreover, the link between the formation of DNA damage following infection and the emergence of cancerous structural variants (SV) in the genome of infected cells remained unexplored. To resolve these gaps, we constructed high-resolution map of genomic H.pylori-induced recurrent break sites. Our data indicated that these sites are ubiquitous across cell types, localized at replication-related fragile sites, and their breakage is dependent on replication. Consistent with that, we found that H.pylori inflicts nucleotide depletion, and that rescuing the nucleotide pool largely reduced H.pylori-induced DNA breaks. Intriguingly, we found that this genotoxic mechanism operates independently of the H.pylori virulence factor, CagA, which was previously implicated in increasing DNA damage by downregulating the DNA damage response. Finally, we show that sites of recurrent H.pylori-mediated breaks coincide with chromosomal deletions observed in patients with intestinal-type GC, and that this link potentially elucidates the persistent transcriptional alterations observed in cancer driver genes. These findings establish the link between H.pylori genotoxicity, and its oncogenic potential.
2024-02-15 | GSE245644 | GEO