The Experts below are selected from a list of 8373 Experts worldwide ranked by ideXlab platform

David M Gilbert - One of the best experts on this subject based on the ideXlab platform.

  • Control of DNA Replication Timing in the 3D genome
    Nature Reviews Molecular Cell Biology, 2019
    Co-Authors: Claire Marchal, Jiao Sima, David M Gilbert
    Abstract:

    The 3D organization of mammalian chromatin was described more than 30 years ago by visualizing sites of DNA synthesis at different times during the S phase of the cell cycle. These early cytogenetic studies revealed structurally stable chromosome domains organized into subnuclear compartments. Active-gene-rich domains in the nuclear interior replicate early, whereas more condensed chromatin domains that are largely at the nuclear and nucleolar periphery replicate later. During the past decade, this spatiotemporal DNA Replication programme has been mapped along the genome and found to correlate with epigenetic marks, transcriptional activity and features of 3D genome architecture such as chromosome compartments and topologically associated domains. But the causal relationship between these features and DNA Replication Timing and the regulatory mechanisms involved have remained an enigma. The recent identification of cis -acting elements regulating the Replication time and 3D architecture of individual Replication domains and of long non-coding RNAs that coordinate whole chromosome Replication provide insights into such mechanisms. Different genomic regions are replicated at different times during the S phase of the cell cycle, forming early- and late-replicating domains that occupy different locations in the nucleus. The recent identification of specific DNA sequences and long non-coding RNAs that regulate DNA Replication Timing is providing key insights into the roles of Replication Timing and into Timing and 3D organization.

  • Replication Timing networks reveal a link between transcription regulatory circuits and Replication Timing control
    Genome Research, 2019
    Co-Authors: Juan Carlos Riveramulia, Sebo Kim, Haitham Gabr, Abhijit Chakraborty, Tamer Kahveci, David M Gilbert
    Abstract:

    DNA Replication occurs in a defined temporal order known as the Replication Timing (RT) program and is regulated during development, coordinated with 3D genome organization and transcriptional activity. However, transcription and RT are not sufficiently coordinated to predict each other, suggesting an indirect relationship. Here, we exploit genome-wide RT profiles from 15 human cell types and intermediate differentiation stages derived from human embryonic stem cells to construct different types of RT regulatory networks. First, we constructed networks based on the coordinated RT changes during cell fate commitment to create highly complex RT networks composed of thousands of interactions that form specific functional subnetwork communities. We also constructed directional regulatory networks based on the order of RT changes within cell lineages, and identified master regulators of differentiation pathways. Finally, we explored relationships between RT networks and transcriptional regulatory networks (TRNs) by combining them into more complex circuitries of composite and bipartite networks. Results identified novel trans interactions linking transcription factors that are core to the regulatory circuitry of each cell type to RT changes occurring in those cell types. These core transcription factors were found to bind cooperatively to sites in the affected Replication domains, providing provocative evidence that they constitute biologically significant directional interactions. Our findings suggest a regulatory link between the establishment of cell-type-specific TRNs and RT control during lineage specification.

  • single cell Replication profiling to measure stochastic variation in mammalian Replication Timing
    Nature Communications, 2018
    Co-Authors: Vishnu Dileep, David M Gilbert
    Abstract:

    Mammalian DNA Replication is regulated via multi-replicon segments that replicate in a defined temporal order during S-phase. Further, early/late Replication of RDs corresponds to active/inactive chromatin interaction compartments. Although Replication origins are selected stochastically, variation in Replication Timing is poorly understood. Here we devise a strategy to measure variation in Replication Timing using DNA copy number in single mouse embryonic stem cells. We find that borders between replicated and unreplicated DNA are highly conserved between cells, demarcating active and inactive compartments of the nucleus. Fifty percent of Replication events deviated from their average Replication time by ± 15% of S phase. This degree of variation is similar between cells, between homologs within cells and between all domains genomewide, regardless of their Replication Timing. These results demonstrate that stochastic variation in Replication Timing is independent of elements that dictate Timing or extrinsic environmental variation. While DNA Replication is temporally regulated during S-phase, variation in Replication Timing is not well understood. Here, the authors measure variation in Replication Timing using DNA copy number in single mouse ESCs and find stochastic variation to be independent of elements that regulate Timing.

  • Replication Timing networks a novel class of gene regulatory networks
    Social Science Research Network, 2018
    Co-Authors: Juan Carlos Riveramulia, Sebo Kim, Haitham Gabr, Tamer Kahveci, David M Gilbert
    Abstract:

    DNA Replication occurs in a defined temporal order known as the Replication-Timing (RT) program and is regulated during development, coordinated with 3D genome organization and transcriptional activity. Here, we exploit genome-wide RT profiles from 15 human cell types and intermediate differentiation stages derived from human embryonic stem cells to construct different types of RT regulatory networks. First, we constructed networks based on the coordinated RT changes during cell fate commitment to create RT networks composed of specific functional sub-network communities. We also constructed directional regulatory networks based on the order of RT changes within cell lineages and identified master regulators of differentiation pathways. Finally, we explored relationships between RT networks and transcriptional regulatory networks (TRNs), by combining them into more complex circuitries of composite and bipartite networks. Our findings show that RT networks can be exploited to dissect the cellular mechanisms that regulate lineage specification and cellular identity maintenance.

  • single cell Replication profiling reveals stochastic regulation of the mammalian Replication Timing program
    bioRxiv, 2017
    Co-Authors: David M Gilbert
    Abstract:

    In mammalian cells, distinct Replication domains (RDs), corresponding to structural units of chromosomes called topologically-associating domains (TADs), replicate at different times during S-phase. Further, early/late Replication of RDs corresponds to active/inactive chromatin interaction compartments. Although Replication origins are selected stochastically, such that each cell is using a different cohort of origins to replicate their genomes, Replication-Timing is regulated independently and upstream of origin selection and evidence suggests that Replication Timing is conserved in consecutive cell cycles. Hence, quantifying the extent of cell-to-cell variation in Replication Timing is central to studies of chromosome structure and function. Here we devise a strategy to measure variation in single-cell Replication Timing using DNA copy number. We find that borders between replicated and un-replicated DNA are highly conserved between cells, demarcating active and inactive compartments of the nucleus. Nonetheless, measurable variation was evident. Surprisingly, we detected a similar degree of variation in Replication Timing from cell-to-cell, between homologues within cells, and between all domains genome-wide regardless of their Replication Timing. These results demonstrate that stochastic variation in Replication Timing is independent of elements that dictate Timing or extrinsic environmental variation.

Mark Groudine - One of the best experts on this subject based on the ideXlab platform.

  • dna Replication Timing analysis of human chromosome 22 at high resolution and different developmental states
    Proceedings of the National Academy of Sciences of the United States of America, 2004
    Co-Authors: Eric J White, Olof Emanuelsson, David Scalzo, Thomas Royce, Steven T Kosak, Edward J Oakeley, Sherman M Weissman, Mark Gerstein, Mark Groudine
    Abstract:

    Duplication of the genome during the S phase of the cell cycle does not occur simultaneously; rather, different sequences are replicated at different times. The Replication Timing of specific sequences can change during development; however, the determinants of this dynamic process are poorly understood. To gain insights into the contribution of developmental state, genomic sequence, and transcriptional activity to Replication Timing, we investigated the Timing of DNA Replication at high resolution along an entire human chromosome (chromosome 22) in two different cell types. The pattern of Replication Timing was correlated with respect to annotated genes, gene expression, novel transcribed regions of unknown function, sequence composition, and cytological features. We observed that chromosome 22 contains regions of early- and late-replicating domains of 100 kb to 2 Mb, many (but not all) of which are associated with previously described chromosomal bands. In both cell types, expressed sequences are replicated earlier than nontranscribed regions. However, several highly transcribed regions replicate late. Overall, the DNA Replication-Timing profiles of the two different cell types are remarkably similar, with only nine regions of difference observed. In one case, this difference reflects the differential expression of an annotated gene that resides in this region. Novel transcribed regions with low coding potential exhibit a strong propensity for early DNA Replication. Although the cellular function of such transcripts is poorly understood, our results suggest that their activity is linked to the Replication-Timing program.

  • genome wide dna Replication profile for drosophila melanogaster a link between transcription and Replication Timing
    Nature Genetics, 2002
    Co-Authors: Dirk Schubeler, David Scalzo, Mark Groudine, Charles Kooperberg, Bas Van Steensel, Jeffrey J Delrow
    Abstract:

    Replication of the genome before mitotic cell division is a highly regulated process that ensures the fidelity of DNA duplication. DNA Replication initiates at specific locations, termed origins of Replication, and progresses in a defined temporal order during the S phase of the cell cycle. The relationship between Replication Timing and gene expression has been the subject of some speculation1. A recent genome-wide analysis in Saccharomyces cerevisiae showed no association between Replication Timing and gene expression2. In higher eukaryotes, the limited number of genomic loci analyzed has not permitted a firm conclusion regarding this association. To explore the relationship between DNA Replication and gene expression in higher eukaryotes, we developed a strategy to measure the Timing of DNA Replication for thousands of genes in a single DNA array hybridization experiment. Using this approach, we generated a genome-wide map of Replication Timing for Drosophila melanogaster. Moreover, by surveying over 40% of all D. melanogaster genes, we found a strong correlation between DNA Replication early in S phase and transcriptional activity. As this correlation does not exist in S. cerevisiae, this interplay between DNA Replication and transcription may be a unique characteristic of higher eukaryotes.

  • genome wide dna Replication profile for drosophila melanogaster a link between transcription and Replication Timing supplemental data
    2002
    Co-Authors: Dirk Schubeler, David Scalzo, Charles Kooperberg, Jeffrey J Delrow, Bas Van Steensel, Mark Groudine
    Abstract:

    Replication of the genome before mitotic cell division is a highly regulated process that ensures the fidelity of DNA duplication. DNA Replication initiates at specific locations, termed origins of Replication, and progresses in a defined temporal order during the S phase of the cell cycle. The relationship between Replication Timing and gene expression has been the subject of some speculation. A recent genome-wide analysis in Saccharomyces cerevisiae showed no association between Replication Timing and gene expression. In higher eukaryotes, the limited number of genomic loci analyzed has not permitted a firm conclusion regarding this association. To explore the relationship between DNA Replication and gene expression in higher eukaryotes, we developed a strategy to measure the Timing of DNA Replication for thousands of genes in a single DNA array hybridization experiment. Using this approach, we generated a genome-wide map of Replication Timing for Drosophila melanogaster. Moreover, by surveying over 40% of all D. melanogaster genes, we found a strong correlation between DNA Replication early in S phase and transcriptional activity. As this correlation does not exist in S. cerevisiae, this interplay between DNA Replication and transcription may be a unique characteristic of higher eukaryotes.

  • long distance control of origin choice and Replication Timing in the human β globin locus are independent of the locus control region
    Molecular and Cellular Biology, 2000
    Co-Authors: Daniel M Cimbora, Mark Groudine, Dirk Schubeler, Andreas Reik, Joan Hamilton, Claire Francastel, E Epner
    Abstract:

    DNA Replication in the human β-globin locus is subject to long-distance regulation. In murine and human erythroid cells, the human locus replicates in early S phase from a bidirectional origin located near the β-globin gene. This Hispanic thalassemia deletion removes regulatory sequences located over 52 kb from the origin, resulting in Replication of the locus from a different origin, a shift in Replication Timing to late S phase, adoption of a closed chromatin conformation, and silencing of globin gene expression in murine erythroid cells. The sequences deleted include nuclease-hypersensitive sites 2 to 5 (5′HS2-5) of the locus control region (LCR) plus an additional 27-kb upstream region. We tested a targeted deletion of 5′HS2-5 in the normal chromosomal context of the human β-globin locus to determine the role of these elements in Replication origin choice and Replication Timing. We demonstrate that the 5′HS2-5-deleted locus initiates Replication at the appropriate origin and with normal Timing in murine erythroid cells, and therefore we conclude that 5′HS2-5 in the classically defined LCR do not control Replication in the human β-globin locus. Recent studies also show that targeted deletion of 5′HS2-5 results in a locus that lacks globin gene expression yet retains an open chromatin conformation. Thus, the Replication Timing of the locus is closely correlated with nuclease sensitivity but not globin gene expression.

Mathew J. Thayer - One of the best experts on this subject based on the ideXlab platform.

  • reciprocal monoallelic expression of asar lncrna genes controls Replication Timing of human chromosome 6
    bioRxiv, 2019
    Co-Authors: Michael B Heskett, Leslie G Smith, Paul T Spellman, Mathew J. Thayer
    Abstract:

    Abstract DNA Replication occurs on mammalian chromosomes in a cell-type distinctive temporal order known as the Replication Timing program. We previously found that disruption of the noncanonical lncRNA genes ASAR6 and ASAR15 results in delayed Replication Timing and delayed mitotic chromosome condensation of human chromosome 6 and 15, respectively. ASAR6 and ASAR15 display random monoallelic expression, and display asynchronous Replication between alleles that is coordinated with other random monoallelic genes on their respective chromosomes. Disruption of the expressed allele, but not the silent allele, of ASAR6 leads to delayed Replication, activation of the previously silent alleles of linked monoallelic genes, and structural instability of human chromosome 6. In this report, we describe a second lncRNA gene (ASAR6-141) on human chromosome 6 that when disrupted results in delayed Replication Timing in cis. ASAR6-141 is subject to random monoallelic expression and asynchronous Replication, and is expressed from the opposite chromosome 6 homolog as ASAR6. ASAR6-141 RNA, like ASAR6 and ASAR15 RNAs, contains a high L1 content and remains associated with the chromosome territory where it is transcribed. Three classes of cis-acting elements control proper chromosome function in mammals: origins of Replication, centromeres; and telomeres, which are responsible for Replication, segregation and stability of all chromosomes. Our work supports a fourth type of essential chromosomal element, “Inactivation/Stability Centers”, which express ASAR lncRNAs responsible for proper Replication Timing, monoallelic expression, and structural stability of each chromosome. Author summary Mammalian cells replicate their chromosomes during a highly ordered and cell type-specific program. Genetic studies have identified two long non-coding RNA genes, ASAR6 and ASAR15, as critical regulators of the Replication Timing program of human chromosomes 6 and 15, respectively. There are several unusual characteristics of the ASAR6 and ASAR15 RNAs that distinguish them from other long non-coding RNAs, including: being very long (>200 kb), lacking splicing of the transcripts, lacking polyadenylation, and being retained in the nucleus on the chromosomes where they are made. ASAR6 and ASAR15 also have the unusual property of being expressed from only one copy of the two genes located on homologous chromosome pairs. Using these unusual characteristics shared between ASAR6 and ASAR15, we have identified a second ASAR lncRNA gene located on human chromosome 6, which we have named ASAR6-141. ASAR6-141 is expressed from the opposite chromosome 6 homolog as ASAR6, and disruption of the expressed allele results in delayed Replication of chromosome 6. ASAR6-141 RNA had previously been annotated as vlinc273. The very long intergenic non-coding (vlinc)RNAs represent a recently annotated class of RNAs that are long (>50 kb), non-spliced, and non-polyadenlyated nuclear RNAs. There are currently >2,700 vlincRNAs expressed from every chromosome, are encoded by >15% of the human genome, and with a few exceptions have no known function. Our results suggest the intriguing possibility that the vlinc class of RNAs may be functioning to control the Replication Timing program of all human chromosomes.

  • reciprocal monoallelic expression of asar lncrna genes controls Replication Timing of human chromosome 6
    Unknown Journal, 2019
    Co-Authors: Michael B Heskett, Leslie G Smith, Paul T Spellman, Mathew J. Thayer
    Abstract:

    DNA Replication occurs on mammalian chromosomes in a cell-type distinctive temporal order known as the Replication Timing program. We previously found that disruption of the noncanonical lncRNA genes ASAR6 and ASAR15 results in delayed Replication Timing and delayed mitotic chromosome condensation of human chromosomes 6 and 15, respectively. ASAR6 and ASAR15 display random monoallelic expression and display asynchronous Replication between alleles that is coordinated with other random monoallelic genes on their respective chromosomes. Disruption of the expressed allele, but not the silent allele, of ASAR6 leads to delayed Replication, activation of the previously silent alleles of linked monoallelic genes, and structural instability of human chromosome 6. In this report, we describe a second lncRNA gene (ASAR6-141) on human chromosome 6 that when disrupted results in delayed Replication Timing in cisASAR6-141 is subject to random monoallelic expression and asynchronous Replication and is expressed from the opposite chromosome 6 homolog as ASAR6 ASAR6-141 RNA, like ASAR6 and ASAR15 RNAs, contains a high L1 content and remains associated with the chromosome territory where it is transcribed. Three classes of cis-acting elements control proper chromosome function in mammals: origins of Replication, centromeres, and telomeres, which are responsible for Replication, segregation, and stability of all chromosomes. Our work supports a fourth type of essential chromosomal element, the "Inactivation/Stability Center," which expresses ASAR lncRNAs responsible for proper Replication Timing, monoallelic expression, and structural stability of each chromosome.

  • dna Replication Timing genome stability and cancer late and or delayed dna Replication Timing is associated with increased genomic instability
    Seminars in Cancer Biology, 2013
    Co-Authors: Nathan Donley, Mathew J. Thayer
    Abstract:

    Normal cellular division requires that the genome be faithfully replicated to ensure that unaltered genomic information is passed from one generation to the next. DNA Replication initiates from thousands of origins scattered throughout the genome every cell cycle; however, not all origins initiate Replication at the same time. A vast amount of work over the years indicates that different origins along each eukaryotic chromosome are activated in early, middle or late S phase. This temporal control of DNA Replication is referred to as the Replication-Timing program. The Replication-Timing program represents a very stable epigenetic feature of chromosomes. Recent evidence has indicated that the Replication-Timing program can influence the spatial distribution of mutagenic events such that certain regions of the genome experience increased spontaneous mutagenesis compared to surrounding regions. This influence has helped shape the genomes of humans and other multicellular organisms and can affect the distribution of mutations in somatic cells. It is also becoming clear that the Replication-Timing program is deregulated in many disease states, including cancer. Aberrant DNA Replication Timing is associated with changes in gene expression, changes in epigenetic modifications and an increased frequency of structural rearrangements. Furthermore, certain Replication Timing changes can directly lead to overt genomic instability and may explain unique mutational signatures that are present in cells that have undergone the recently described processes of “chromothripsis” and “kataegis”. In this review, we will discuss how the normal Replication Timing program, as well as how alterations to this program, can contribute to the evolution of the genomic landscape in normal and cancerous cells.

  • engineering translocations with delayed Replication evidence for cis control of chromosome Replication Timing
    Human Molecular Genetics, 2005
    Co-Authors: Kevin S Breger, Leslie Smith, Mathew J. Thayer
    Abstract:

    Certain chromosome rearrangements, found in cancer cells or in cells exposed to ionizing radiation, exhibit a chromosome-wide delay in Replication Timing (DRT) that is associated with a delay in mitotic chromosome condensation (DMC). We have developed a chromosome engineering strategy that allows the generation of chromosomes with this DRT/DMC phenotype. We found that approximately 10% of inter-chromosomal translocations induced by two distinct mechanisms, site-specific recombination mediated by Cre or non-homologous end joining of DNA double-strand breaks induced by I-Sce1, result in DRT/DMC. Furthermore, on certain balanced translocations only one of the derivative chromosomes displays the phenotype. Finally, we show that the engineered DRT/DMC chromosomes acquire gross chromosomal rearrangements at an increased rate when compared with non-DRT/DMC chromosomes. These results indicate that the DRT/DMC phenotype is not the result of a stochastic process that could occur at any translocation breakpoint or as an epigenetic response to chromosome damage. Instead, our data indicate that the Replication Timing of certain derivative chromosomes is regulated by a cis-acting mechanism that delays both initiation and completion of DNA synthesis along the entire length of the chromosome. Because chromosomes with DRT/DMC are common in tumor cells and in cells exposed to ionizing radiation, we propose that DRT/DMC represents a common mechanism responsible for the genomic instability found in cancer cells and for the persistent chromosomal instability associated with cells exposed to ionizing radiation.

Conrad A Nieduszynski - One of the best experts on this subject based on the ideXlab platform.

  • Cohesin-Mediated Genome Architecture Does Not Define DNA Replication Timing Domains
    'MDPI AG', 2019
    Co-Authors: Oldach P, Conrad A Nieduszynski
    Abstract:

    3D genome organization is strongly predictive of DNA Replication Timing in mammalian cells. This work tested the extent to which loop-based genome architecture acts as a regulatory unit of Replication Timing by using an auxin-inducible system for acute cohesin ablation. Cohesin ablation in a population of cells in asynchronous culture was shown not to disrupt patterns of Replication Timing as assayed by Replication sequencing (RepliSeq) or BrdU-focus microscopy. Furthermore, cohesin ablation prior to S phase entry in synchronized cells was similarly shown to not impact Replication Timing patterns. These results suggest that cohesin-mediated genome architecture is not required for the execution of Replication Timing patterns in S phase, nor for the establishment of Replication Timing domains in G1. View Full-Text

  • Cohesin-Mediated Genome Architecture Does Not Define DNA Replication Timing Domains
    MDPI AG, 2019
    Co-Authors: Phoebe Oldach, Conrad A Nieduszynski
    Abstract:

    3D genome organization is strongly predictive of DNA Replication Timing in mammalian cells. This work tested the extent to which loop-based genome architecture acts as a regulatory unit of Replication Timing by using an auxin-inducible system for acute cohesin ablation. Cohesin ablation in a population of cells in asynchronous culture was shown not to disrupt patterns of Replication Timing as assayed by Replication sequencing (RepliSeq) or BrdU-focus microscopy. Furthermore, cohesin ablation prior to S phase entry in synchronized cells was similarly shown to not impact Replication Timing patterns. These results suggest that cohesin-mediated genome architecture is not required for the execution of Replication Timing patterns in S phase, nor for the establishment of Replication Timing domains in G1

  • Rapid high-resolution measurement of DNA Replication Timing by droplet digital PCR.
    Nucleic acids research, 2018
    Co-Authors: Dzmitry G. Batrakou, Emma D. Heron, Conrad A Nieduszynski
    Abstract:

    Genomes are replicated in a reproducible temporal pattern. Current methods for assaying allele Replication Timing are time consuming and/or expensive. These include high-throughput sequencing which can be used to measure DNA copy number as a proxy for allele Replication Timing. Here, we use droplet digital PCR to study DNA Replication Timing at multiple loci in budding yeast and human cells. We establish that the method has temporal and spatial resolutions comparable to the high-throughput sequencing approaches, while being faster than alternative locus-specific methods. Furthermore, the approach is capable of allele discrimination. We apply this method to determine relative Replication Timing across Timing transition zones in cultured human cells. Finally, multiple samples can be analysed in parallel, allowing us to rapidly screen kinetochore mutants for perturbation to centromere Replication Timing. Therefore, this approach is well suited to the study of locus-specific Replication and the screening of cis- and trans-acting mutants to identify mechanisms that regulate local genome Replication Timing.

  • Rapid high-resolution measurement of DNA Replication Timing by droplet digital PCR
    2017
    Co-Authors: Dzmitry G. Batrakou, Emma D. Heron, Conrad A Nieduszynski
    Abstract:

    Genomes are replicated in a reproducible temporal pattern. Current methods for assaying allele Replication Timing are time consuming and/or expensive. These include high-throughput sequencing which can be used to measure DNA copy number as a proxy for allele Replication Timing. Here we use droplet digital PCR to study DNA Replication Timing at multiple loci in budding yeast and human cells. We establish that the method has temporal and spatial resolutions that can exceed high-throughput sequencing approaches, while being more efficient than alternative methods. Furthermore, the approach is capable of allele discrimination. We apply this method to determine relative Replication Timing across Timing transition zones in cultured human cells. Finally, multiple samples can be analysed in parallel, allowing us to rapidly screen kinetochore mutants for perturbation to centromere Replication Timing. Therefore, this approach is well suited to the study of locus-specific Replication and the screening of cis- and trans-acting mutants to identify mechanisms that regulate genome Replication Timing.

  • dna Replication Timing influences gene expression level
    Journal of Cell Biology, 2017
    Co-Authors: Carolin A Muller, Conrad A Nieduszynski
    Abstract:

    Eukaryotic genomes are replicated in a reproducible temporal order; however, the physiological significance is poorly understood. We compared Replication Timing in divergent yeast species and identified genomic features with conserved Replication times. Histone genes were among the earliest replicating loci in all species. We specifically delayed the Replication of HTA1-HTB1 and discovered that this halved the expression of these histone genes. Finally, we showed that histone and cell cycle genes in general are exempt from Rtt109-dependent dosage compensation, suggesting the existence of pathways excluding specific loci from dosage compensation mechanisms. Thus, we have uncovered one of the first physiological requirements for regulated Replication time and demonstrated a direct link between Replication Timing and gene expression.

Oscar M Aparicio - One of the best experts on this subject based on the ideXlab platform.

  • the rpd3 sin3 histone deacetylase regulates Replication Timing and enables intra s origin control in saccharomyces cerevisiae
    Molecular and Cellular Biology, 2004
    Co-Authors: Jennifer G Aparicio, Christopher J Viggiani, Daniel G Gibson, Oscar M Aparicio
    Abstract:

    The Replication of eukaryotic genomes follows a temporally staged program, in which late origin firing often occurs within domains of altered chromatin structure(s) and silenced genes. Histone deacetylation functions in gene silencing in some late-replicating regions, prompting an investigation of the role of histone deacetylation in Replication Timing control in Saccharomyces cerevisiae. Deletion of the histone deacetylase Rpd3 or its interacting partner Sin3 caused early activation of late origins at internal chromosomal loci but did not alter the initiation Timing of early origins or a late-firing, telomere-proximal origin. By delaying initiation relative to the earliest origins, Rpd3 enables regulation of late origins by the intra-S Replication checkpoint. RPD3 deletion suppresses the slow S phase of clb5Δ cells by enabling late origins to fire earlier, suggesting that Rpd3 modulates the initiation Timing of many origins throughout the genome. Examination of factors such as Ume6 that function together with Rpd3 in transcriptional repression indicates that Rpd3 regulates origin initiation Timing independently of its role in transcriptional repression. This supports growing evidence that for much of the S. cerevisiae genome transcription and Replication Timing are not linked.

  • the rpd3 sin3 histone deacetylase regulates Replication Timing and enables intra s origin control in saccharomyces cerevisiae
    Molecular and Cellular Biology, 2004
    Co-Authors: Jennifer G Aparicio, Christopher J Viggiani, Daniel G Gibson, Oscar M Aparicio
    Abstract:

    The Replication of eukaryotic genomes follows a temporally staged program, in which late origin firing often occurs within domains of altered chromatin structure(s) and silenced genes. Histone deacetylation functions in gene silencing in some late-replicating regions, prompting an investigation of the role of histone deacetylation in Replication Timing control in Saccharomyces cerevisiae. Deletion of the histone deacetylase Rpd3 or its interacting partner Sin3 caused early activation of late origins at internal chromosomal loci but did not alter the initiation Timing of early origins or a late-firing, telomere-proximal origin. By delaying initiation relative to the earliest origins, Rpd3 enables regulation of late origins by the intra-S Replication checkpoint. RPD3 deletion suppresses the slow S phase of clb5Delta cells by enabling late origins to fire earlier, suggesting that Rpd3 modulates the initiation Timing of many origins throughout the genome. Examination of factors such as Ume6 that function together with Rpd3 in transcriptional repression indicates that Rpd3 regulates origin initiation Timing independently of its role in transcriptional repression. This supports growing evidence that for much of the S. cerevisiae genome transcription and Replication Timing are not linked.