Gene-to-gene coordinated regulation of transcription and alternative splicing by 3D chromatin remodeling upon NF-κB activation
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ABSTRACT:
PROVIDER: PRJNA978519 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24793100.fastq.gz | Fastqsanger.gz | |||
| SRR24793101.fastq.gz | Fastqsanger.gz | |||
| SRR24793102.fastq.gz | Fastqsanger.gz | |||
| SRR24793103.fastq.gz | Fastqsanger.gz | |||
| SRR24793086.fastq.gz | Fastqsanger.gz |
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Project description:The p65/RelA factor of NF-κB plays a pivotal role in coordinating gene expression in response to diverse stimuli, including viral infections. At the chromatin level, p65/RelA governs gene transcription and alternative splicing (AS) through promoter enrichment and genomic exon occupancy, respectively. However, the mechanisms underlying the coordination of these processes remain elusive. In this study, we employed the HTLV-1 Tax viral oncoprotein, a potent activator of NF-κB, to investigate the integrative relationship between 3D chromatin architecture and NF-κB-regulated AS. Our analysis revealed that Tax induces a significant reorganization of the 3D genome, resulting in the formation of multigene complexes that comprise genes co-regulated in transcription and in AS. Notably, we found that the Tax-induced gene-gene contact between the two master genes NFKBIA and RELA is associated with their differential regulation in gene expression and alternative splicing, respectively. Through dCas9-mediated approaches, we demonstrated that NFKBIA-RELA interaction is required for alternative splicing regulation and is caused by an intragenic enrichment of p65/RelA on RELA. Via this mechanism, Tax promotes the expression of the splice isoform RELAE6 that exhibits specific gene transactivation capacity at the protein level. Our findings shed light on new regulatory mechanisms upon HTLV-1 Tax and underscore the crucial role of p65/RelA in coordinated regulation of NF-κB-responsive genes at both transcriptional and alternative splicing levels in the context of the 3D genome.
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Project description:The p65/RelA factor of NF-κB plays a pivotal role in coordinating gene expression in response to diverse stimuli, including viral infections. At the chromatin level, p65/RelA governs gene transcription and alternative splicing (AS) through promoter enrichment and genomic exon occupancy, respectively. However, the mechanisms underlying the coordination of these processes remain elusive. In this study, we employed the HTLV-1 Tax viral oncoprotein, a potent activator of NF-κB, to investigate the integrative relationship between 3D chromatin architecture and NF-κB-regulated AS. Our analysis revealed that Tax induces a significant reorganization of the 3D genome, resulting in the formation of multigene complexes that comprise genes co-regulated in transcription and in AS. Notably, we found that the Tax-induced gene-gene contact between the two master genes NFKBIA and RELA is associated with their differential regulation in gene expression and alternative splicing, respectively. Through dCas9-mediated approaches, we demonstrated that NFKBIA-RELA interaction is required for alternative splicing regulation and is caused by an intragenic enrichment of p65/RelA on RELA. Via this mechanism, Tax promotes the expression of the splice isoform RELAE6 that exhibits specific gene transactivation capacity at the protein level. Our findings shed light on new regulatory mechanisms upon HTLV-1 Tax and underscore the crucial role of p65/RelA in coordinated regulation of NF-κB-responsive genes at both transcriptional and alternative splicing levels in the context of the 3D genome.
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Project description:Gene-to-gene coordinated regulation of transcription and alternative splicing by 3D chromatin remodeling upon NF-κB activation
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Project description:Gene-to-gene coordinated regulation of transcription and alternative splicing by 3D chromatin remodeling upon NF-κB activation
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Project description:NF-κB has an essential role in innate immune response and inflammation and is involved in cancer development and progression. We apply the SEC-PCP-SILAC method incorporating metabolic labeling, size exclusion chromatography and protein correlation profiling to construct a complex network of interactome rearrangement in response to NF-κB modulation in breast cancer cells. Our interaction network represents a complex insight into the dynamics of MCF-7 protein interactome associated with NF-κB pathway. Our dataset could serve as a basis for future studies characterizing role of NF-κB in breast cancer cellular pathways. This PRIDE project includes results from SILAC labeled and label-free replicates from the SEC-PCP-SILAC analysis of protein complexes in MCF-7 cells with inhibited and uninhibited NF-κB pathway, results from the immunoprecipitation experiment aimed at interaction partners of NF-κB factor RELA, analysis of total proteome after NF-κB inhibition, and results from SEC fractionation of untreated and unlabeled MCF-7 cells.
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2015-07-01 | E-GEOD-65170 | biostudies-arrayexpress
Project description:Transcriptional profiling of human control and Néstor-Guillermo Progeria Syndrome (NGPS) mesenchymal stem cells (MSCs). Somatic cell reprogramming involves rejuvenation of adult cells and relies on the ability to erase age-associated molecular marks. Accordingly, reprogramming efficiency declines with ageing, and age-associated features such as genetic instability, cell senescence or telomere shortening negatively affect this process. However, the regulatory mechanisms that constitute age-associated barriers for cell reprogramming remain largely unknown. Here, by using cells from patients with premature ageing, we demonstrate that NF-κB activation is a critical barrier for the generation of induced pluripotent stem cells (iPSCs) in ageing. We show that NF-κB repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-κB hyperactivation impairs generation of iPSCs by eliciting reprogramming repressors DOT1L and YY1, reinforcing cell senescence signals and down-regulating pluripotency genes. We also show that genetic and pharmacological NF-κB inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Néstor-Guillermo Progeria Syndrome (NGPS) and Hutchinson-Gilford Progeria Syndrome (HGPS) patients, as well as from normal aged donors. Finally, we demonstrate that DOT1L inhibition in vivo ameliorates the accelerated ageing phenotype and extends lifespan in a progeroid animal model. Collectively, our results provide evidence for a novel role of NF-κB in the control of cell fate transitions and reinforce the interest of studying age-associated molecular impairments to implement cell reprogramming methodologies, and to identify new targets of rejuvenation strategies. Control and NGPS MSCs were differentiated into bone in the presence or absence of sodium salicylate. Total RNA was extracted and global gene expression was analyzed.
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Project description:MTD project_description Inflammation and decreased stem cell function characterize organism aging, yet the relationship between these factors remains incompletely understood. This study shows that aged hematopoietic stem and progenitor cells exhibit increased ground-stage NF-κB activity, which enhances their responsiveness to undergo differentiation and loss of self-renewal in response to inflammation. The study identifies Rad21/cohesin as a critical mediator of NF-κB signals, by increasing chromatin accessibility of inter-/intra-genic and enhancer regions. Rad21/NF-κB are required for normal differentiation, but limit self-renewal of hematopoietic stem cells (HSCs) during aging and inflammation in an NF-κB dependent manner. HSCs from aged mice fail to downregulate Rad21/cohesin and inflammation/differentiation inducing signals in the resolution phase after acute inflammation. and The inhibition of cohesin/NF-κB is sufficient to revert the hypersensitivity of aged HSPCs to inflammation-induced differentiation. During aging, myeloid-biased HSCs with disrupted and naturally occurring reduced expression of Rad21/cohesin are increasingly selected over lymphoid-biased HSCs. Together, Rad21/cohesin mediated NF-κB signaling limits HSPC function during aging and selects for cohesin deficient HSCs with myeloid skewed differentiation.
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