DNA replication timing alterations in genetic diseases
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ABSTRACT:
PROVIDER: PRJNA760943 | ENA |
REPOSITORIES: ENA
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Project description:DNA replication timing alterations in genetic diseases
| PRJNA760942 | ENA
Project description:Alterations in DNA replication timing identify TP63 as a novel marker of progeroid diseases
| PRJNA385178 | ENA
Project description:Human DNA Replication Timing Variation
| PRJNA598743 | ENA
Project description:Human DNA Replication Timing Variation
| PRJNA598744 | ENA
Project description:Fused-in-sarcoma (FUS) encodes an RNA-binding protein with diverse roles in transcriptional activation and RNA splicing. While oncogenic fusions of FUS and transcription factor DNA-binding domains are associated with soft tissue sarcomas, dominant mutations in FUS cause amyotrophic lateral sclerosis (ALS). FUS has also been implicated in genome maintenance. However, the underlying mechanisms are unknown.
Here, we applied gene editing, functional reconstitution and integrated proteomic and transcriptomics to illuminate roles for FUS in DNA replication and repair. Consistent with a supportive role in DNA double-strand break (DSB) repair FUS deficient cells exhibited subtle alterations in the recruitment and retention of DSB-associated factors, including 53BP1 and BRCA1. FUS-/- cells also exhibited reduced proliferative potential that correlated with reduced replication fork speed, diminished loading of pre-replication complexes, enhanced micronucleus formation, and attenuated expression and splicing of S-phase associated genes. Finally, FUS-deficient cells exhibited genome-wide alterations in DNA replication timing that were reversed upon reeexpression of FUS cDNA. FUS-dependent replication domains were enriched in transcriptionally active chromatin and FUS was required for the timely replication of transcriptionally active DNA. These findings suggest that alterations DNA replication kinetics and programming contribute to genome instability and functional defects in FUS deficient cells.
2021-06-24 | MSV000087698 | MassIVE
Project description:The temporal order of DNA replication is modified during differentiation, but when a replication timing program is established and what alterations occur in vivo during embryogenesis are not known. Here we used zebrafish embryos to generate genome-wide, high-resolution replication timing maps throughout development. Unexpectedly, a non-random and defined replication timing program was evident in the rapid cell cycles before the midblastula transition. The majority of the genome undergoes dynamic shifts in replication timing throughout development as the timing program is decompressed, with many abrupt timing changes occurring during lineage specification. Strikingly, the long arm of chromosome 4 undergoes a developmentally regulated switch to late replication, reminiscent of mammalian X chromosome inactivation. This analysis also revealed a strong relationship between early replication and epigenetic marks at enhancers. Collectively, these data reveal the major changes in replication timing that occur during zebrafish embryogenesis, and demonstrate its dynamic regulation during vertebrate development.
2017-04-13 | GSE85713 | GEO
Project description:Progeroid syndromes are rare genetic disorders that phenotypically resemble natural aging. Despite identification of causal mutations, mechanisms that generate their clinical manifestations remain elusive. Here, we identified a DNA replication timing (RT) signature that distinguishes progeroid syndromes from normal aging and identifies TP63 gene as a new disease marker. Abnormal TP63 RT appears early during differentiation of progeroid iPSCs and is associated with altered gene variant expression. Our findings demonstrate the utility of RT signatures to identify novel biomarkers not detected by other methods, reveal abnormal TP63 RT as an early event in progeroid disease progression and offer TP63 gene regulation as a potential therapeutic target.
2017-11-16 | GSE98472 | GEO
Project description:Progeroid syndromes are rare genetic disorders that phenotypically resemble natural aging. Despite identification of causal mutations, mechanisms that generate their clinical manifestations remain elusive. Here, we identified a DNA replication timing (RT) signature that distinguishes progeroid syndromes from normal aging and identifies TP63 gene as a new disease marker. Abnormal TP63 RT appears early during differentiation of progeroid iPSCs and is associated with altered gene variant expression. Our findings demonstrate the utility of RT signatures to identify novel biomarkers not detected by other methods, reveal abnormal TP63 RT as an early event in progeroid disease progression and offer TP63 gene regulation as a potential therapeutic target.
2017-11-16 | GSE98471 | GEO
Project description:DNA replication is initiated at multiple sites or origins enriched with AT-rich sequences at various times during the S-phase. While current studies of genome-wide DNA replication profiles have focused on the timing of replication and the location of origins, the efficiency of replication/firing at various origins remains unclear. In this study, we show different efficiencies of DNA replication at various loci by using ORF-specific DNA microarrays. DNA copy-number increases as a function of time at individual loci are approximated to near-sigmoidal models for estimation of replication initiation and completion timings in HU-challenged cells. Duplicating times (from initiation to completion) vary from loci to loci, partly contributing to various firing efficiencies at origins. DNA replication timing profiles are strikingly similar to the reported patterns of enriched ssDNA, suggesting that majority stalled forks are restored for resumption of DNA replication. Although the DNA replication timing profiles are disrupted in HU-challenged cds1? cells, ~85% of potential origins overlapped with those found in wild type cells, significantly, most of which represents inefficiently fired origins in wild type cells. Together, our result indicates that replication checkpoint plays a role in monitoring efficient origins and thus maintaining global DNA replication patterns in HU-challenged cells. Keywords: WT or Cds1 HU synchronized cells released in HU free media and harvested at different time points vs WT or Cds1 synchronized with HU for 3 hrs. We analyzed 32 arrays for WT and 38 arrays for Cds1 cells which were synchronized with HU and released in HU free media and harvested at different time points. At least two biological repeats were done for each time points.
2007-08-14 | E-GEOD-6977 | biostudies-arrayexpress
Project description:Fused in sarcoma (FUS) encodes a low complexity RNA-binding protein with diverse roles in transcriptional activation and RNA processing. While oncogenic fusions of FUS and transcription factor DNA-binding domains are associated with soft tissue sarcomas, dominant mutations in FUS cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). FUS has also been implicated in DNA double-strand break repair (DSBR) and genome maintenance. However, the underlying mechanisms are unknown. Here we employed quantitative proteomics, transcriptomics, and DNA copy number analysis (Sort-Seq), in conjunction with FUS-/- cells to ascertain roles of FUS in genome protection. FUS-/- cells exhibited alterations in the recruitment and retention of DSBR factors BRCA1 and 53BP1 but were not overtly sensitive to genotoxins. By contrast, FUS-deficient cells had reduced proliferative potential that correlated with reduced replication fork speed, diminished loading of pre-replication complexes, and attenuated expression of S-phase associated genes. FUS interacted with lagging strand DNA synthesis factors and other replisome components, but did not translocate with active replication forks. Using a Sort-Seq workflow, we show that FUS contributes to genome-wide control of DNA replication timing and is essential for the early replication of transcriptionally active DNA. These findings illuminate new roles for FUS in DNA replication initiation and timing that may contribute to genome instability and functional defects in cells harboring disease-associated FUS fusions.
2020-05-13 | GSE147784 | GEO