NAT10-mediated β-hydroxybutyrylation Rewires Genomic 3D Conformation and Replication Timing [Replication-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA735959 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14758215_1.fastq.gz | Fastqsanger.gz | |||
| SRR14758215_2.fastq.gz | Fastqsanger.gz | |||
| SRR14758216_1.fastq.gz | Fastqsanger.gz | |||
| SRR14758216_2.fastq.gz | Fastqsanger.gz | |||
| SRR14758217_1.fastq.gz | Fastqsanger.gz |
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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.
2021-09-08 | GSE175731 | GEO
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.
2021-09-08 | GSE176359 | GEO
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.
2024-07-04 | GSE179410 | GEO
Project description:NAT10-mediated β-hydroxybutyrylation Rewires Genomic 3D Conformation and Replication Timing
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Project description:As obligate parasites, viruses need to navigate a variety of cellular regulatory systems while infecting and replicating in the host cell. Post-transcriptional modifications have recently emerged as an important layer of regulation of viral RNA function. For example, our lab and others have shown that the RNA modification N6-methyladenosine (m6A) can enhance the replication of multiple viruses in cis, including Human Immunodeficiency virus 1 (HIV-1), Influenza A virus, SV40 and Kaposi's sarcoma-associated herpesvirus (KSHV). Recent reports have revealed the presence of another RNA modification, N4-acetylcytidine (ac4C) on cellular mRNAs and have shown that ac4C can enhance mRNA stability and translation. Here, we demonstrate that ac4C is present at multiple sites on HIV-1 mRNAs and on the viral genomic RNA. Through ac4C RNA immunoprecipitation (RNA-IP) and RNA-seq, we found ac4C on HIV-1 mRNAs as well as the virion genomic RNA, with ac4C sites in the coding regions of the pol, env, nef genes, and the trans-activation response (TAR) hairpin. Phenotypically, we observe that increasing the expression level of the ac4C acetyltransferase NAT10 leads to an increase in viral replication that is dependent on the RNA binding and enzymatic domains of NAT10. Moreover, both CRISPR-depletion of NAT10 (ΔNAT10) and treatment with the small molecule NAT10 inhibitor Remodelin, diminishes HIV-1 replication in T cells. Lastly, silent mutations introduced to prevent ac4C deposition on the viral genome indeed diminished HIV-1 replication. Our data suggest that HIV-1 has evolved to incorporate ac4C in essential viral gene coding regions and regulatory RNA structures, and that NAT10-dependent ac4C addition enhances HIV-1 replication.
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Project description:In this experiment, we aim to examine the role of NAT10 inhibition in Hutchinson-Gilford progeria syndrome (HGPS), a rare but devastating premature ageing syndrome caused by a mutation in the LMNA gene. NAT10 inhibition improves HGPS cellular phenotypes by releasing Transportin-1 (TNPO1) from the cytoplasm, restoring the TNPO1 pathway and allowing hnRNPA1 and NUP153 nuclear import, TPR anchorage at the nuclear pore complexes and RanGTP gradient re-balancing. We have promoted NAT10 inhibition by two ways in normal or patient derived primary skin fibroblasts; the NAT10 inhibitor Remodelin, and an siRNA directly targeting NAT10 (siNAT10). In addition, we have also used an siRNA against TNPO1 and a combined siTNPO1 and siNAT10 treatment. This is a 2-factor design, with treatment (Remodelin vs untreated, or siNAT10 vs siCT) and condition (HGPS vs normal fibroblasts) as the two conditions. Transcriptional profiling was performed using HumanHT-12 v4 Expression BeadChip microarrays, and all conditions were run in triplicate.
2018-06-25 | E-MTAB-6651 | biostudies-arrayexpress
Project description:The early embryonic divisions of many organisms, including fish, flies and frogs are characterised by a very rapid S-phase caused by high rates of replication initiation. In somatic cells, S-phase is much longer due to both a reduction in the total number of initiation events and the imposition of a temporal order of origin activation. The physiological importance of changes in the rate and timing of replication initiation in S-phase remains unclear. Here we assess the importance of the temporal control of replication initiation using a conditional system in budding yeast to drive the early replication of all origins in a single cell cycle. We show that global early replication disrupts the expression of over a quarter of all genes. By deleting individual origins we show that delaying replication is sufficient to restore normal gene expression, directly establishing replication timing control in this regulation. Global early replication disrupts nucleosome positioning and transcription factor binding during S-phase, suggesting that the rate of S-phase is important to regulate the chromatin landscape. Together these data provide new insight into the role of a temporal order of origin firing for coordinating replication, gene expression and chromatin establishment as occurs in the early embryo.
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Project description:DNA replication stress is the major cause of genomic instability in human cells. The ataxia telangiectasia and Rad3-related kinase (ATR) plays an essential role in the cellular response to replication stress and inhibition of ATR has emerged as therapeutic strategy for the treatment of cancer. However, the ATR-dependent signaling in the cellular response to replication stress has not been systematically investigated. Here, we employ quantitative mass spectrometry-based proteomics to decipher the ATR-dependent phosphorylation events in response to pathological replication stress induced by hydroxyurea. Our data define the substrate spectrum of ATR and identify several novel putative ATR substrates. In addition, we demonstrate that ATR-inhibition fundamentally rewires cellular signaling networks leading to the prominent activation of different pathways including the ATM-driven double strand break repair.
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