Distinct classes of genes behave as either drivers or dependents of replication timing switches.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE63592 | GEO | 2015/06/03
SECONDARY ACCESSION(S): PRJNA268362
REPOSITORIES: GEO
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Project description:Duplication of the genome in mammalian cells occurs in a defined temporal order referred as its replication-timing program (RT). RT is regulated in units of 400-800 Kb referred as replication domains (RDs) and changes dynamically during development. Changes in RT are generally coordinated with transcriptional competence and changes in sub-nuclear position. We generated genome-wide RT profiles for 29 distinct human cell types including embryonic stem cell (hESC)-derived, primary cells and established cell lines representing intermediate stages of endoderm, mesoderm, ectoderm and neural crest (NC) development. We identified clusters of RDs that replicate at unique times in each stage (RT signatures). Surprisingly, transcriptome data revealed that, despite an overall correlation between early replication and transcriptional activity, most genes that switched RT during differentiation can be expressed when late replicating. Intriguingly, this class of genes was nonetheless induced to high expression levels prior to a late to early RT switch and down-regulated after the switch back to late replication. These results clarify the complex relationship between transcription and RT and identify classes of genes that behave as potential drivers of the RT switch vs. those that may depend upon an RT switch for transcriptional induction.
2015-05-28 | GSE63428 | GEO
Project description:Duplication of the genome in mammalian cells occurs in a defined temporal order referred as its replication-timing program (RT). RT is regulated in units of 400-800 Kb referred as replication domains (RDs) and changes dynamically during development. Changes in RT are generally coordinated with transcriptional competence and changes in sub-nuclear position. We generated genome-wide RT profiles for 29 distinct human cell types including embryonic stem cell (hESC)-derived, primary cells and established cell lines representing intermediate stages of endoderm, mesoderm, ectoderm and neural crest (NC) development. We identified clusters of RDs that replicate at unique times in each stage (RT signatures). Surprisingly, transcriptome data revealed that, despite an overall correlation between early replication and transcriptional activity, most genes that switched RT during differentiation can be expressed when late replicating. Intriguingly, this class of genes was nonetheless induced to high expression levels prior to a late to early RT switch and down-regulated after the switch back to late replication. These results clarify the complex relationship between transcription and RT and identify classes of genes that behave as potential drivers of the RT switch vs. those that may depend upon an RT switch for transcriptional induction. Genome-wide replication timing profiles were constructed from 60 human samples covering 29 distinct cell types including embryonic stem cell (hESC)-derived, primary cells and established cell lines representing intermediate stages of endoderm, mesoderm, ectoderm and neural crest (NC) development.
2015-05-28 | E-GEOD-63428 | biostudies-arrayexpress
Project description:DNA replication occurs in units of chromatin higher order organization (Topologically Associating Domains, or TADs; replication domains, or RDs), which self-organize in 3D into sub-nuclear compartments of early or late replicating chromatin. However, identification of cis-elements regulating replication timing (RT) and sub-nuclear compartments has been a major challenge in the field. Through an extensive series of CRISPR mediated deletion and inversions at a pluripotency associated domain (DppA2/4) in mouse embryonic stem cells (mESCs), we have identified cis-regulatory “early replication control elements” (ERCEs) that mediate early replication and A/B compartmentalization. We show that CTCF/cohesin loops, including the TAD boundaries, were dispensable, and multiple internal DNA segments were necessary for the domain’s early replication in a partially redundant fashion. These segments were also sufficient to maintain early replication in the context of large inversions, irrespective of TAD boundaries. High-resolution capture Hi-C of this region revealed three sites of major contact that also displayed prominent chromatin features. Targeted deletion of all three contact points, which do not include the major mapped replication origins, caused a complete shift to late replication and association with compartment B, equivalent to the switch during lineage commitment. Individual and pair-wise deletions confirmed their partial redundancy and interdependency in giving rise to domain-wise RT patterns, and suggest the importance of long-range interactions. ERCEs are enriched in properties of strong or super-enhancers, and regulate gene expression, although transcription itself is not sufficient in driving early replication. In sum, our results have revealed the first cis-elements regulating the temporal and spatial control of DNA replication that is independent of transcription.
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Project description:DNA replication occurs in units of chromatin higher order organization (Topologically Associating Domains, or TADs; replication domains, or RDs), which self-organize in 3D into sub-nuclear compartments of early or late replicating chromatin. However, identification of cis-elements regulating replication timing (RT) and sub-nuclear compartments has been a major challenge in the field. Through an extensive series of CRISPR mediated deletion and inversions at a pluripotency associated domain (DppA2/4) in mouse embryonic stem cells (mESCs), we have identified cis-regulatory “early replication control elements” (ERCEs) that mediate early replication and A/B compartmentalization. We show that CTCF/cohesin loops, including the TAD boundaries, were dispensable, and multiple internal DNA segments were necessary for the domain’s early replication in a partially redundant fashion. These segments were also sufficient to maintain early replication in the context of large inversions, irrespective of TAD boundaries. High-resolution capture Hi-C of this region revealed three sites of major contact that also displayed prominent chromatin features. Targeted deletion of all three contact points, which do not include the major mapped replication origins, caused a complete shift to late replication and association with compartment B, equivalent to the switch during lineage commitment. Individual and pair-wise deletions confirmed their partial redundancy and interdependency in giving rise to domain-wise RT patterns, and suggest the importance of long-range interactions. ERCEs are enriched in properties of strong or super-enhancers, and regulate gene expression, although transcription itself is not sufficient in driving early replication. In sum, our results have revealed the first cis-elements regulating the temporal and spatial control of DNA replication that is independent of transcription.
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Project description:DNA replication occurs in units of chromatin higher order organization (Topologically Associating Domains, or TADs; replication domains, or RDs), which self-organize in 3D into sub-nuclear compartments of early or late replicating chromatin. However, identification of cis-elements regulating replication timing (RT) and sub-nuclear compartments has been a major challenge in the field. Through an extensive series of CRISPR mediated deletion and inversions at a pluripotency associated domain (DppA2/4) in mouse embryonic stem cells (mESCs), we have identified cis-regulatory “early replication control elements” (ERCEs) that mediate early replication and A/B compartmentalization. We show that CTCF/cohesin loops, including the TAD boundaries, were dispensable, and multiple internal DNA segments were necessary for the domain’s early replication in a partially redundant fashion. These segments were also sufficient to maintain early replication in the context of large inversions, irrespective of TAD boundaries. High-resolution capture Hi-C of this region revealed three sites of major contact that also displayed prominent chromatin features. Targeted deletion of all three contact points, which do not include the major mapped replication origins, caused a complete shift to late replication and association with compartment B, equivalent to the switch during lineage commitment. Individual and pair-wise deletions confirmed their partial redundancy and interdependency in giving rise to domain-wise RT patterns, and suggest the importance of long-range interactions. ERCEs are enriched in properties of strong or super-enhancers, and regulate gene expression, although transcription itself is not sufficient in driving early replication. In sum, our results have revealed the first cis-elements regulating the temporal and spatial control of DNA replication that is independent of transcription.
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Project description:DNA replication occurs in units of chromatin higher order organization (Topologically Associating Domains, or TADs; replication domains, or RDs), which self-organize in 3D into sub-nuclear compartments of early or late replicating chromatin. However, identification of cis-elements regulating replication timing (RT) and sub-nuclear compartments has been a major challenge in the field. Through an extensive series of CRISPR mediated deletion and inversions at a pluripotency associated domain (DppA2/4) in mouse embryonic stem cells (mESCs), we have identified cis-regulatory “early replication control elements” (ERCEs) that mediate early replication and A/B compartmentalization. We show that CTCF/cohesin loops, including the TAD boundaries, were dispensable, and multiple internal DNA segments were necessary for the domain’s early replication in a partially redundant fashion. These segments were also sufficient to maintain early replication in the context of large inversions, irrespective of TAD boundaries. High-resolution capture Hi-C of this region revealed three sites of major contact that also displayed prominent chromatin features. Targeted deletion of all three contact points, which do not include the major mapped replication origins, caused a complete shift to late replication and association with compartment B, equivalent to the switch during lineage commitment. Individual and pair-wise deletions confirmed their partial redundancy and interdependency in giving rise to domain-wise RT patterns, and suggest the importance of long-range interactions. ERCEs are enriched in properties of strong or super-enhancers, and regulate gene expression, although transcription itself is not sufficient in driving early replication. In sum, our results have revealed the first cis-elements regulating the temporal and spatial control of DNA replication that is independent of transcription.
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Project description:DNA replication occurs in units of chromatin higher order organization (Topologically Associating Domains, or TADs; replication domains, or RDs), which self-organize in 3D into sub-nuclear compartments of early or late replicating chromatin. However, identification of cis-elements regulating replication timing (RT) and sub-nuclear compartments has been a major challenge in the field. Through an extensive series of CRISPR mediated deletion and inversions at a pluripotency associated domain (DppA2/4) in mouse embryonic stem cells (mESCs), we have identified cis-regulatory “early replication control elements” (ERCEs) that mediate early replication and A/B compartmentalization. We show that CTCF/cohesin loops, including the TAD boundaries, were dispensable, and multiple internal DNA segments were necessary for the domain’s early replication in a partially redundant fashion. These segments were also sufficient to maintain early replication in the context of large inversions, irrespective of TAD boundaries. High-resolution capture Hi-C of this region revealed three sites of major contact that also displayed prominent chromatin features. Targeted deletion of all three contact points, which do not include the major mapped replication origins, caused a complete shift to late replication and association with compartment B, equivalent to the switch during lineage commitment. Individual and pair-wise deletions confirmed their partial redundancy and interdependency in giving rise to domain-wise RT patterns, and suggest the importance of long-range interactions. ERCEs are enriched in properties of strong or super-enhancers, and regulate gene expression, although transcription itself is not sufficient in driving early replication. In sum, our results have revealed the first cis-elements regulating the temporal and spatial control of DNA replication that is independent of transcription.
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