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| Status |
Public on Jul 01, 2015 |
| Title |
NF-κB activation impairs somatic cell reprogramming in ageing [IKBA-SR] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| Summary |
Transcriptional profiling of human Néstor-Guillermo Progeria Syndrome (NGPS) fibroblasts control, treated with sodium salicylate or transduced with Ikappa B alpha super-repressor.
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.
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| Overall design |
Human NGPS fibroblasts were treated with sodium salicylate, transduced with Ikappa B alpha super-repressor or left untreated. RNA was extracted and transcriptional profiling was obtained with GeneChip Human Gene 2.0 ST Arrays.
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| Contributor(s) |
Osorio FG, Soria-Valles C, Freije JM, Lopez-Otin C |
| Citation(s) |
26214134 |
| |
| Submission date |
Jan 21, 2015 |
| Last update date |
Sep 30, 2015 |
| Contact name |
Jose M.P. Freije |
| E-mail(s) |
jmpf@uniovi.es
|
| Phone |
34-985106281
|
| Organization name |
Universidad de Oviedo
|
| Department |
Bioquimica y Biologia Molecular
|
| Lab |
IUOPA
|
| Street address |
C/ Fernando Bongera s/n
|
| City |
Oviedo |
| State/province |
Asturias |
| ZIP/Postal code |
33006 |
| Country |
Spain |
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| Platforms (1) |
| GPL19251 |
[HuGene-2_0-st] Affymetrix Human Gene 2.0 ST Array [probe set (exon) version] |
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| Samples (3) |
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| This SubSeries is part of SuperSeries: |
| GSE65173 |
NF-κB activation impairs somatic cell reprogramming in ageing |
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| Relations |
| BioProject |
PRJNA273327 |
