Chromatin conformation and transcriptional activity are permissive regulators of DNA replication initiation in Drosophila
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ABSTRACT:
PROVIDER: PRJNA473140 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:We replaced the endogenous histones of Drosophila melanogaster with either histones containing an H3K9R mutation or histones containing an H4K16R mutation to interrogate established genome-wide correlations between chromatin state, transcription, and DNA replication timing. We performed total RNA-seq in H4K16R males and females to investigate the role of H4K16 in dosage compensation of the male X chromosome. We found that H4K16 directly promotes hyper-expression of the male X chromosome in Drosophila. To generate replication timing profiles, we performed Repli-seq in HWT males and females, H4K16R males and females, and H3K9R females. We found that H3K9 promotes late replication of the pericentromeric heterochromatin and H4K16 promotes early replication of the male X chromosome.
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Project description:Chromatin structure has emerged as a key contributor to spatial and temporal control over the initiation of DNA replication. However, despite genome-wide correlations between early replication of gene-rich, accessible euchromatin and late replication of gene-poor, inaccessible heterochromatin, a causal relationship between chromatin structure and replication initiation remains elusive. Here, we combined histone gene engineering and whole-genome sequencing in Drosophila to determine how perturbing chromatin structure affects replication initiation. We found that most pericentric heterochromatin remains late replicating in H3K9R mutants, even though H3K9R pericentric heterochromatin is depleted of HP1a, more accessible, and transcriptionally active. These data indicate that HP1a loss, increased chromatin accessibility, and elevated transcription do not result in early replication of heterochromatin. Nevertheless, a small amount of pericentric heterochromatin with increased accessibility replicates earlier in H3K9R mutants. Transcription is de-repressed in these regions of advanced replication but not in those regions of the H3K9R mutant genome that replicate later, suggesting that transcriptional repression may contribute to late replication. We also explored relationships among chromatin, transcription, and replication in euchromatin by analyzing H4K16R mutants. In Drosophila, the X Chromosome gene expression is up-regulated twofold and replicates earlier in XY males than it does in XX females. We found that H4K16R mutation prevents normal male development and abrogates hyperexpression and earlier replication of the male X, consistent with previously established genome-wide correlations between transcription and early replication. In contrast, H4K16R females are viable and fertile, indicating that H4K16 modification is dispensable for genome replication and gene expression.
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Project description:Spatiotemporal regulation of chromatin replication (replication timing, RT) in eukaryotes is critical to maintain the genomic integrity. Here we focused on epigenetic mechanisms in rewiring genomic 3D conformation and replication timing. The results show that the novel lysine β-hydroxybutyrylation (Kbhb) modifications accelerates chromatin replication without inducing replication defects. This effect was mediated by the NAT10, a novel b-hydroxybutyryl-transferase, through regulating the association of NAT10 and CTCF with chromatin. Depletion of NAT10 and NAT10-mediated Kbhb dramatically reduce chromatin-bound NAT10 and CTCF, resulting in reorganization of genomic 3D conformation with enhanced trans- and cis-interaction in Hi-C matrix, with elevated proportion of A compartments, and with reorganized TADs boundaries. Moreover, reorganization of genomic 3D conformation contributes to rewire replication timing. These results support models in which NAT10-mediated β-hydroxybutyrylation coordinates genomic 3D conformation reorganization with replication timing alteration, and emphatically address the concept that epigenetic mechanisms reconcile genomic 3D conformation with replication timing.
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Project description:MX1 is a well-characterized interferon-induced antiviral gene. MX1 is activated by viral infection due to interferon production in cells. We treated non-permissive Huh7 cells and permissive HRP4 cells with interferon. We compared the expression of genes induced by interferon to determine host factors affecting HCV replication.
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Project description:Spatiotemporal regulation of chromatin replication (replication timing, RT） in eukaryotes is critical to maintain the genomic integrity. Here we focused on epigenetic mechanisms in rewiring genomic 3D conformation and replication timing. The results show that the novel lysine β-hydroxybutyrylation (Kbhb) modifications accelerates chromatin replication without inducing replication defects. This effect was mediated by the NAT10, a novel b-hydroxybutyryl-transferase, through regulating the association of NAT10 and CTCF with chromatin. Depletion of NAT10 and NAT10-mediated Kbhb dramatically reduce chromatin-bound NAT10 and CTCF, resulting in reorganization of genomic 3D conformation with enhanced trans- and cis-interaction in Hi-C matrix, with elevated proportion of A compartments, and with reorganized TADs boundaries. Moreover, reorganization of genomic 3D conformation contributes to rewire replication timing. These results support models in which NAT10-mediated β-hydroxybutyrylation coordinates genomic 3D conformation reorganization with replication timing alteration, and emphatically address the concept that epigenetic mechanisms reconcile genomic 3D conformation with replication timing.
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Project description:Spatiotemporal regulation of chromatin replication (replication timing, RT） in eukaryotes is critical to maintain the genomic integrity. Here we focused on epigenetic mechanisms in rewiring genomic 3D conformation and replication timing. The results show that the novel lysine β-hydroxybutyrylation (Kbhb) modifications accelerates chromatin replication without inducing replication defects. This effect was mediated by the NAT10, a novel b-hydroxybutyryl-transferase, through regulating the association of NAT10 and CTCF with chromatin. Depletion of NAT10 and NAT10-mediated Kbhb dramatically reduce chromatin-bound NAT10 and CTCF, resulting in reorganization of genomic 3D conformation with enhanced trans- and cis-interaction in Hi-C matrix, with elevated proportion of A compartments, and with reorganized TADs boundaries. Moreover, reorganization of genomic 3D conformation contributes to rewire replication timing. These results support models in which NAT10-mediated β-hydroxybutyrylation coordinates genomic 3D conformation reorganization with replication timing alteration, and emphatically address the concept that epigenetic mechanisms reconcile genomic 3D conformation with replication timing.
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Project description:NAT10-mediated β-hydroxybutyrylation Rewires Genomic 3D Conformation and Replication Timing [Replication-seq]
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Project description:DNA replication in mammalian cells occurs in a defined temporal order during S phase, known as the replication timing programme. Replication timing is developmentally regulated and correlated with chromatin conformation and local transcriptional potential. Here we present RT profiles of unprecedented temporal resolution in two human embryonic stem cell lines, human colon carcinoma line HCT116 as well as F1 sub-species hybrid mouse embryonic stem cells and their neural progenitor derivatives. Strong enrichment of nascent DNA in fine temporal windows reveals a remarkable degree of cell to cell conservation in replication timing and patterns of replication genome-wide. We identify 5 patterns of replication in all cell types, consistent with varying degrees of initiation efficiency. Zones of replication initiation were found throughout S phase and resolved to ~50kb precision. Temporal transition regions were resolved into segments of uni-directional replication punctuated with small zones of inefficient initiation. Small and large valleys of convergent replication were consistent with either termination or broadly distributed initiation, respectively. RT correlated with chromatin compartment across all cell types but correlations of initiation time to chromatin domain boundaries and histone marks were cell type specific. Haplotype phasing revealed previously unappreciated regions of allele-specific and allele-independent asynchronous replication. Allele-independent asynchrony was associated with large transcribed genes that resemble common fragile sites. Altogether, these data reveal a remarkably deterministic temporal choreography of DNA replication in mammalian cells.
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