H3K4 methylation buffers the effects of metabolic adaptation on replication initiation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA714566 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR13963706.fastq.gz | Fastqsanger.gz | |||
| SRR13963707.fastq.gz | Fastqsanger.gz | |||
| SRR13963708.fastq.gz | Fastqsanger.gz | |||
| SRR13963709.fastq.gz | Fastqsanger.gz |
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Project description:In this study, we unravel a previously unknown function of H3K4 methylation (H3K4me; a universal marker of actively transcribed genes that also accumulates around replication origins) as a capacitor that masks the adverse effects of metabolic adaptation by facilitating initiation of replication.
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Project description:H3K4 methylation at active genes mitigates transcription-replication conflicts during replication stress
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Project description:Methylated H3K4 (H3K4me) is highly conserved and has been widely considered to be involved in transcriptional control. However, this once popular model was recently challenged by multiple groups, because blocking this modification does not appreciably affect transcription. Thus, the function of the H3K4me remains unclear. To investigate how H3K4 methylation influences the processes of transcription and replication under HU-stress, we used chromatin immunoprecipitation-sequencing (ChIP-seq) to identify genomic sites of active transcription marked by Rpb3, a subunit of RNA Polymerase II, and sites of replication pausing marked by DNA Pol2, a subunit of DNA Polymerase e. Our data lead us to the surprising conclusion that H3K4me pauses the progression of replication forks, and we propose that high levels of H3K4me deposited by high transcriptional activity result in a large cushioning effect on fork progression to protect against transcription-replication collisions (TRCs), which cause genome instability.
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Project description:DNA replication initiation is made possible by the assembly of pre- replication complexes (Pre-RCs) at genomic locations called DNA replication initiation sites (origins) during G1-phase. Although there are no conserved characteristics of metazoan origins on which Pre-RCs form, previous findings suggest that origins are strongly associated with open, active chromatin regions of the genome such as promoters, enhancers, and active histone marks. However, over a third of transcriptionally silent genes associate with DNA replication initiation activity in mESC cells, and most of these genes are bound and repressed by the Polycomb repressive complex 2 (PRC2) through the repressive H3K27me3 mark. This is the strongest observed association of an epigenetic regulator element with replication origin activity. Thus, I wished to ask whether Polycomb-mediated gene repression plays a direct role in the recruitment of DNA replication origins activity to silent genes. I comprehensively characterized the consequences of PRC2 catalytic activity (EZH2 subunit) depletion on the activity of DNA replication origins in mESC through a genome-wide evaluation. My findings suggest that absence of EZH2 results in increased DNA replication initiation activity at EZH2-bound sites. Interestingly, the increase in DNA replication initiation activity does not correlate with transcriptional de-repression or acquisition of the activating marks H3K4me3 and H3K27ac but loss of the repressive H3K27me3 mark leading to increased accessibility of chromatin.
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Project description:We develop a high-throughput nucleoside analog incorporation sequencing assay and identify thousands of early replication initiation zones (ERIZs) in both mouse and human cells. The identified ERIZs fall in open chromatin compartments while are mutually exclusive with transcription elongation and occupy mainly non-transcribed regions adjacent to transcribed regions. Furthermore, we reveal that RNA polymerase II actively redistributes the chromatin-encircled mini-chromosome maintenance (MCM) complex but not the origin-recognition complex (ORC) to actively restrict early DNA replication initiation outside of transcribed regions. The coupling of RNA polymerase II and MCM is further validated by detected MCM accumulation and DNA replication initiation after RNA polymerase II stalling via anchoring nuclease-dead Cas9 at the transcribed genes. Importantly, we also find that the orchestration of DNA replication initiation by transcription can efficiently prevent gross DNA damage.
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Project description:The hexameric DNA helicase MCM (Mcm2-7) is a central regulatory target in eukaryotic replication. Chromatin-bound MCM is kept inactive during G1 phase and subsequently activated in S phase to initiate replication. During this transition, the only known chemical change on the Mcm2-7 proteins is the gain of multi-site phosphorylation that promotes recruitment of co-factors. As replication initiation is tied intimately to multiple biological cues, additional changes on these proteins can provide a second regulatory point. Here we describe a new MCM modification cycle mediated by SUMO that enables a negative regulation of replication initiation. We show that all MCM subunits undergo sumoylation upon loading at origins in G1 phase prior to MCM phosphorylation. Then bulk MCM sumoylation is lost as MCM phosphorylation rises. The pattern of MCM sumoylation suggests a negative role in replication. Indeed, increasing MCM sumoylation delays genome-wide replication initiation. Mechanistically, this is partly due to enhancing the recruitment of a conserved phosphatase that delays MCM phosphorylation and activation. By revealing a new MCM modification cycle and its role in replication, our findings suggest a new model, in which MCM sumoylation counterbalances kinase-based regulation to ensure accurate control of replication initiation.
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Project description:Genomic mapping of DNA replication origins (ORIs) in mammals provides a powerful means for understanding the regulatory complexity of our genome. Here we combine a genome-wide approach to identify preferential sites of DNA replication initiation at 0.4% of the mouse genome with detailed molecular analysis at distinct classes of ORIs according to their location relative to the genes. Our study reveals that 85% of the replication initiation sites in mouse embryonic stem (ES) cells are associated with transcriptional units. Nearly half of the identified ORIs map at promoter regions and, interestingly, ORI density strongly correlates with promoter density, reflecting the coordinated organisation of replication and transcription in the mouse genome. Detailed analysis of ORI activity showed that CpG island promoter-ORIs are the most efficient ORIs in ES cells and both ORI specification and firing efficiency are maintained across cell types. Remarkably, the distribution of replication initiation sites at promoter-ORIs exactly parallels that of transcription start sites (TSS) suggesting a co-evolution of the regulatory regions driving replication and transcription. Moreover, we found that promoter-ORIs are significantly enriched in CAGE tags derived from early embryos relative to all promoters. This association implies that transcription initiation early in development sets the probability of ORI activation unveiling a new hallmark in ORI efficiency regulation in mammalian cells. Two biological replicates of lambda-exonuclease treated short nascent strands (100-600 or 300-800 nt in length) were co-hybridised with genomic DNA from the same cells to tiled genomic array covering 10.1 Mb of the mouse genome (Agilent Technologies)
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Project description:The Replication-initiation determinant protein (RepID) modulates replication by recruiting CUL4 to chromatin
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Project description:Loss of Ezh2 function reshapes DNA replication initiation landscape
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