PKCα-LSD1-NF-κB Signaling Cascade Is Crucial for Epigenetic Control of the Inflammatory Response
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ABSTRACT:
PROVIDER: PRJNA422239 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5713220_1.fastq.gz | Fastqsanger.gz | |||
| SRR5713220_2.fastq.gz | Fastqsanger.gz | |||
| SRR5713221_1.fastq.gz | Fastqsanger.gz | |||
| SRR5713221_2.fastq.gz | Fastqsanger.gz | |||
| SRR5713222_1.fastq.gz | Fastqsanger.gz |
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Project description:The inflammatory response mediated by NF-κB signaling is essential for host defense against pathogens. Although the components and regulatory mechanism of NF-κB signaling have been well-studied, molecular basis for the epigenetic regulation of the inflammatory response is poorly understood. Here, we identify a new signaling axis of PKCα- LSD1-NF-κB p65 which is critical for activation and amplification of the inflammatory response and triggering systemic inflammatory diseases. In response to excessive inflammatory stimuli, PKCα translocates to the nucleus and phosphorylates LSD1. Phosphorylation of LSD1 is required for its interaction with p65 and facilitates demethylation of p65 leading to enhanced protein stability. Genome-wide analysis reveals a critical role of LPS-induced LSD1 phosphorylation in the transcriptional activation of NF-κB target genes. Together, we demonstrate that PKCα-LSD1-NF-κB signaling cascade is crucial for epigenetic control of the inflammatory response.
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Project description:The inflammatory response mediated by NF-κB signaling is essential for host defense against pathogens. Although the components and regulatory mechanism of NF-κB signaling have been well-studied, molecular basis for the epigenetic regulation of the inflammatory response is poorly understood. Here, we identify a new signaling axis of PKCα- LSD1-NF-κB p65 which is critical for activation and amplification of the inflammatory response and triggering systemic inflammatory diseases. In response to excessive inflammatory stimuli, PKCα translocates to the nucleus and phosphorylates LSD1. Phosphorylation of LSD1 is required for its interaction with p65 and facilitates demethylation of p65 leading to enhanced protein stability. Genome-wide analysis reveals a critical role of LPS-induced LSD1 phosphorylation in the transcriptional activation of NF-κB target genes. Together, we demonstrate that PKCα-LSD1-NF-κB signaling cascade is crucial for epigenetic control of the inflammatory response.
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Project description:PKCα-LSD1-NF-κB Signaling Cascade Is Crucial for Epigenetic Control of the Inflammatory Response [ChIP-Seq]
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Project description:Transcriptional profiling of human control and Néstor-Guillermo Progeria Syndrome (NGPS) fibroblasts and induced pluripotent stem cells (iPSCs). 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 fibroblasts were reprogrammed. RNA was extracted and transcriptional profiling was obtained with GeneChip Human Exon 1.0 ST Arrays.
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