Decoding the Replication Timing Program in Zebrafish: The Role of Rif1
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ABSTRACT:
PROVIDER: PRJNA938098 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23602344_1.fastq.gz | Fastqsanger.gz | |||
| SRR23602344_2.fastq.gz | Fastqsanger.gz | |||
| SRR23602345_1.fastq.gz | Fastqsanger.gz | |||
| SRR23602345_2.fastq.gz | Fastqsanger.gz | |||
| SRR23602346_1.fastq.gz | Fastqsanger.gz |
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Project description:Deregulated DNA replication is a major contributor to human developmental disorders and cancer, yet our understanding of how replication is coordinated with changes in transcription and chromatin structure is limited. Our lab has employed the zebrafish model to investigate the mechanisms driving changes in the replication timing program during development. Previous studies have identified changes in replication timing patterns from the onset of zygotic transcription through gastrulation in zebrafish embryos. The protein Rif1 is crucial for replication timing in a wide range of eukaryotes, yet its role in establishing the replication timing program and chromatin structure during early vertebrate development is not well understood. Using Rif1 mutant zebrafish and performing RNA sequencing and whole-genome replication timing analysis, we found that Rif1 mutants were viable but had a defect in female sex determination. Interestingly, Rif1 loss primarily affected DNA replication timing after gastrulation, while its impact on transcription was more pronounced during zygotic genome activation. Our results indicate that Rif1 has distinct roles in regulating DNA replication and transcription at different stages of development.
2023-08-15 | GSE225957 | GEO
Project description:Three-dimensional genome organisation and replication timing are known to be correlated, however, it remains unknown whether nuclear architecture overall plays an instructive role in the replication-timing program and, if so, how. Here we demonstrate that RIF1 is a molecular hub that co-regulates both processes. Both nuclear organisation and replication timing depend upon the interaction between RIF1 and PP1. However, whereas nuclear architecture requires the full complement of RIF1 and its interaction with PP1, replication timing is not sensitive to RIF1 dosage. RIF1’s role in replication timing also extends beyond its interaction with PP1. Availing of this separation-of-function approach, we have therefore identified in RIF1 dual function the molecular bases of the co-dependency of the replication-timing program and nuclear architecture.
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Project description:DNA replication is spatially and temporally regulated during S-phase. DNA replication timing is established in early G1-phase at a point referred to as TDP (timing decision point). We show that Rif1 (Rap1-interacting-factor1), originally identified as a telomere binding factor in yeast, is a critical determinant of the replication timing program in human cells. Depletion of Rif1 results in specific loss of mid-S replication foci profiles, stimulation of initiation events in early S-phase and changes in long-range replication timing domain structures. Overall replication timing is shifted toward mid-S in both directions, suggesting that replication timing regulation is abrogated in the absence of Rif1. Rif1 tightly binds to nuclear insoluble structures at late-M to early-G1 and regulates the chromatin-loop sizes. Furthermore, Rif1 colocalizes specifically with the mid-S replication foci. Thus, Rif1 establishes the mid-S replication domains that are restrained from being activated at early S-phase. Our results indicate that Rif1 plays crucial roles in determining the replication timing domain structures through regulating higher-order chromatin architecture. HeLa cells (ATCC), with a total of 4 individual replicates
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Project description:DNA replication is spatially and temporally regulated during S-phase. DNA replication timing is established in early G1-phase at a point referred to as TDP (timing decision point). We show that Rif1 (Rap1-interacting-factor1), originally identified as a telomere binding factor in yeast, is a critical determinant of the replication timing program in human cells. Depletion of Rif1 results in specific loss of mid-S replication foci profiles, stimulation of initiation events in early S-phase and changes in long-range replication timing domain structures. Overall replication timing is shifted toward mid-S in both directions, suggesting that replication timing regulation is abrogated in the absence of Rif1. Rif1 tightly binds to nuclear insoluble structures at late-M to early-G1 and regulates the chromatin-loop sizes. Furthermore, Rif1 colocalizes specifically with the mid-S replication foci. Thus, Rif1 establishes the mid-S replication domains that are restrained from being activated at early S-phase. Our results indicate that Rif1 plays crucial roles in determining the replication timing domain structures through regulating higher-order chromatin architecture.
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Project description:The mammalian DNA replication timing (RT) program is crucial for the proper functioning and integrity of the genome. The best-known mechanism for controlling RT is the suppression of late origins of replication in heterochromatin by RIF1. Here, we report that in antigen-activated, hypermutating murine B lymphocytes, RIF1 binds predominantly to early-replicating active chromatin and promotes early replication, but plays a minor role in regulating replication origin activity, gene expression and genome organization in B cells. Furthermore, we find that RIF1 functions in a complementary and non-epistatic manner with minichromosome maintenance (MCM) proteins to establish early RT signatures genome-wide and, specifically, to ensure the early replication of highly transcribed genes. These findings reveal new layers of regulation within the B cell RT program, driven by the coordinated activity of RIF1 and MCM proteins.
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Project description:Chromosomal DNA replication involves the coordinated activity of hundreds to thousands of replication origins. Individual replication origins are subject to epigenetic regulation of their activity during S-phase, resulting in differential efficiencies and timings of replication initiation during S-phase. This regulation is thought to involve chromatin structure and organization into timing domains with differential ability to recruit limiting replication factors. Rif1 has recently been identified as a genome-wide regulator of replication timing in fission yeast and in mammalian cells. However, previous studies in budding yeast have suggested that Rif1’s role in controlling replication timing may be limited to subtelomeric domains and derives from its established role in telomere length regulation. We have analyzed replication timing by analyzing BrdU incorporation genome-wide, and report that Rif1 regulates the timing of late/dormant replication origins throughout the S. cerevisiae genome. Analysis of pfa4∆ cells, which are defective in palmitoylation and membrane association of Rif1, suggests that replication timing regulation by Rif1 is independent of its role in localizing telomeres to the nuclear periphery. Intra-S checkpoint signaling is intact in rif1∆ cells, and checkpoint-defective mec1∆ cells do not comparably deregulate replication timing, together indicating that Rif1 regulates replication timing through a mechanism independent of this checkpoint. Our results indicate that the Rif1 mechanism regulates origin timing irrespective of proximity to a chromosome end, and suggest instead that telomere sequences merely provide abundant binding sites for proteins that recruit Rif1. Still, the abundance of Rif1 binding in telomeric domains may facilitate Rif1-mediated repression of non-telomeric origins that are more distal from centromeres. 30 total samples: (6 samples - BrdU- HU arrest 45min with 2 replicates, strains: WT, rif1 delta, pfa4 delta) (12 samples -S-phase BrdU time course with 2 replicates at 25 and 35 min, strains: WT, rif1 delta, mec1_100) (12 samples - S-phase BrdU time course with 2 replicates at 25 and 35 min, strains: sml1 delta, sml1 delta rif1 delta, sml1 delta mec1 delta)
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Project description:The mammalian DNA replication timing (RT) program is crucial for the proper functioning and integrity of the genome. The best-known mechanism for controlling RT is the suppression of late origins of replication in heterochromatin by RIF1. Here, we report that in antigen-activated, hypermutating B lymphocytes, RIF1 binds predominantly to early-replicating active chromatin, regulates early origin firing and promotes early replication. However, RIF1 has a minor role in gene expression and genome organization in B cells. Furthermore, we find that RIF1 functions in a complementary and non-epistatic manner with minichromosome maintenance (MCM) proteins to establish early RT signatures genome-wide and, specifically, to ensure the early replication of highly transcribed genes. These findings reveal a new layer of regulation within the B cell RT program, driven by the coordinated activity of RIF1 and MCM proteins.
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Project description:The mammalian DNA replication timing (RT) program is crucial for the proper functioning and integrity of the genome. The best-known mechanism for controlling RT is the suppression of late origins of replication in heterochromatin by RIF1. Here, we report that in antigen-activated, hypermutating B lymphocytes, RIF1 binds predominantly to early-replicating active chromatin, regulates early origin firing and promotes early replication. However, RIF1 has a minor role in gene expression and genome organization in B cells. Furthermore, we find that RIF1 functions in a complementary and non-epistatic manner with minichromosome maintenance (MCM) proteins to establish early RT signatures genome-wide and, specifically, to ensure the early replication of highly transcribed genes. These findings reveal a new layer of regulation within the B cell RT program, driven by the coordinated activity of RIF1 and MCM proteins.
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Project description:The mammalian DNA replication timing (RT) program is crucial for the proper functioning and integrity of the genome. The best-known mechanism for controlling RT is the suppression of late origins of replication in heterochromatin by RIF1. Here, we report that in antigen-activated, hypermutating B lymphocytes, RIF1 binds predominantly to early-replicating active chromatin, regulates early origin firing and promotes early replication. However, RIF1 has a minor role in gene expression and genome organization in B cells. Furthermore, we find that RIF1 functions in a complementary and non-epistatic manner with minichromosome maintenance (MCM) proteins to establish early RT signatures genome-wide and, specifically, to ensure the early replication of highly transcribed genes. These findings reveal a new layer of regulation within the B cell RT program, driven by the coordinated activity of RIF1 and MCM proteins.
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Project description:The mammalian DNA replication timing (RT) program is crucial for the proper functioning and integrity of the genome. The best-known mechanism for controlling RT is the suppression of late origins of replication in heterochromatin by RIF1. Here, we report that in antigen-activated, hypermutating B lymphocytes, RIF1 binds predominantly to early-replicating active chromatin, regulates early origin firing and promotes early replication. However, RIF1 has a minor role in gene expression and genome organization in B cells. Furthermore, we find that RIF1 functions in a complementary and non-epistatic manner with minichromosome maintenance (MCM) proteins to establish early RT signatures genome-wide and, specifically, to ensure the early replication of highly transcribed genes. These findings reveal a new layer of regulation within the B cell RT program, driven by the coordinated activity of RIF1 and MCM proteins.
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