Dynamic Multi-omics Profiling Unveils Bimodal Epigenetic Roles of Chromatin O-GlcNAc modification in Premature Senescence Program [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1252776 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33234575_1.fastq.gz | Fastqsanger.gz | |||
| SRR33234575_2.fastq.gz | Fastqsanger.gz | |||
| SRR33234576_1.fastq.gz | Fastqsanger.gz | |||
| SRR33234576_2.fastq.gz | Fastqsanger.gz | |||
| SRR33234577_1.fastq.gz | Fastqsanger.gz |
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Project description:Cellular senescence, a recognized instigator of tumorigenesis and age-associated disorders, can be precipitated by characteristic alterations in gene expression profiles. However, the underlying mechanisms that precise orchestrate the expression of senescence-related genes are still elusive. Here, we employed a time-series approach using a chemical genomics multi-omics strategy to panoramically investigate the role of O-GlcNAc chromatin-associated proteins (OCPs) throughout the process of oncogene-induced senescence (OIS) in human primary fibroblasts. The progression of OIS is associated with the dynamic accumulation of chromatin O-GlcNAc modification, which facilitates cells commitment to senescence. Through the integration of dynamic analyses of transcriptome and epigenome profiles, we can demonstrate that OCPs experience genomic occupation shifts across diverse epigenetic chromatin states, and display bimodal sequential regulatory activity within the senescence transcriptome. Mechanistically, O-GlcNAc aids in the formation of bimodal epigenetic regulatory complexes (TF-SWI/SNF and NuRD), which dictate the gene expression patterns related to both the senescence-associated secretory phenotype (SASP) and cell cycle arrest. Additionally, we pinpointed O-GlcNAc JUN and GATAD2A as key regulators affecting the phenotypes of OIS in both in vitro and in vivo models of senescence and tumorigenesis. Our findings on the dynamic behavior and chromatin organization principles of O-GlcNAc epigenetic factors provide insights into the senescence process and enable potential therapeutic manipulation of the senescence phenotype.
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Project description:Cellular senescence, a recognized instigator of tumorigenesis and age-associated disorders, can be precipitated by characteristic alterations in gene expression profiles. However, the underlying mechanisms that precise orchestrate the expression of senescence-related genes are still elusive. Here, we employed a time-series approach using a chemical genomics multi-omics strategy to panoramically investigate the role of O-GlcNAc chromatin-associated proteins (OCPs) throughout the process of oncogene-induced senescence (OIS) in human primary fibroblasts. The progression of OIS is associated with the dynamic accumulation of chromatin O-GlcNAc modification, which facilitates cells commitment to senescence. Through the integration of dynamic analyses of transcriptome and epigenome profiles, we can demonstrate that OCPs experience genomic occupation shifts across diverse epigenetic chromatin states, and display bimodal sequential regulatory activity within the senescence transcriptome. Mechanistically, O-GlcNAc aids in the formation of bimodal epigenetic regulatory complexes (TF-SWI/SNF and NuRD), which dictate the gene expression patterns related to both the senescence-associated secretory phenotype (SASP) and cell cycle arrest. Additionally, we pinpointed O-GlcNAc JUN and GATAD2A as key regulators affecting the phenotypes of OIS in both in vitro and in vivo models of senescence and tumorigenesis. Our findings on the dynamic behavior and chromatin organization principles of O-GlcNAc epigenetic factors provide insights into the senescence process and enable potential therapeutic manipulation of the senescence phenotype.
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Project description:Cellular senescence, a recognized instigator of tumorigenesis and age-associated disorders, can be precipitated by characteristic alterations in gene expression profiles. However, the underlying mechanisms that precise orchestrate the expression of senescence-related genes are still elusive. Here, we employed a time-series approach using a chemical genomics multi-omics strategy to panoramically investigate the role of O-GlcNAc chromatin-associated proteins (OCPs) throughout the process of oncogene-induced senescence (OIS) in human primary fibroblasts. The progression of OIS is associated with the dynamic accumulation of chromatin O-GlcNAc modification, which facilitates cells commitment to senescence. Through the integration of dynamic analyses of transcriptome and epigenome profiles, we can demonstrate that OCPs experience genomic occupation shifts across diverse epigenetic chromatin states, and display bimodal sequential regulatory activity within the senescence transcriptome. Mechanistically, O-GlcNAc aids in the formation of bimodal epigenetic regulatory complexes (TF-SWI/SNF and NuRD), which dictate the gene expression patterns related to both the senescence-associated secretory phenotype (SASP) and cell cycle arrest. Additionally, we pinpointed O-GlcNAc JUN and GATAD2A as key regulators affecting the phenotypes of OIS in both in vitro and in vivo models of senescence and tumorigenesis. Our findings on the dynamic behavior and chromatin organization principles of O-GlcNAc epigenetic factors provide insights into the senescence process and enable potential therapeutic manipulation of the senescence phenotype.
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Project description:Dynamic Multi-omics Profiling Unveils Bimodal Epigenetic Roles of Chromatin O-GlcNAc modification in Premature Senescence Program [ChIP-seq]
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Project description:Dynamic Multi-omics Profiling Unveils Bimodal Epigenetic Roles of Chromatin O-GlcNAc modification in Premature Senescence Program [BiSulfite-seq]
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Project description:Dysfunctional mitochondria and generation of reactive oxygen species (ROS) promote chronic diseases, which have spurred interest in the molecular mechanisms underlying these conditions. Previously, we have demonstrated that disruption of post-translational modification of proteins with β-linked N-acetylglucosamine (O- glcnAcylation) via overexpression of the O-glcnAc–regulating enzymes O- glcnAc transferase (OGT) or O- glcnAcase (OGA) impairs mitochondrial function. Here, we report that sustained alterations in O- glcnAcylation either by pharmacological or genetic manipulation also alters metabolic function. Sustained O-glcnAc elevation in SH-SY5Y neuroblastoma cells increased OGA expression and reduced cellular respiration and ROS generation. Cells with elevated O-glcnAc levels had elongated mitochondria and increased mitochondrial membrane potential, and RNA-Seq in SH-SY5Y cells indicated transcriptome reprogramming and down regulation of the NRF2-mediated antioxidant response. Sustained O-glcnAcylation in mice brain and liver validated the metabolic phenotypes observed in the cells, and OGT knockdown in the liver elevated ROS levels, impaired respiration, and increased the NRF2 antioxidant response. Moreover, elevated O-glcnAc levels promoted weight loss and lowered respiration in mice and skewed the mice toward carbohydrate-dependent metabolism as determined by indirect calorimetry. In summary, sustained elevation in O-glcnAcylation coupled with increased OGA expression reprograms energy metabolism, a finding that has potential implications for the etiology, development, and management of metabolic diseases.
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