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Chromosomal Instability and Molecular Defects in Induced Pluripotent Stem Cells with Nijmegen Breakage Syndrome

ABSTRACT: Nijmegen breakage syndrome (NBS) results from the absence of the NBS1 protein, responsible for detection of DNA double-strand breaks (DSBs). NBS is characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. Here we show successful reprogramming of NBS fibroblasts into induced pluripotent stem cells (NBS-iPSCs). Our data suggest a strong selection for karyotypically normal fibroblasts to go through the reprogramming process. NBS-iPSCs then acquire numerous chromosomal aberrations and show a delayed response to DSB induction. Furthermore, NBS-iPSCs display slower growth, mitotic inhibition, a reduced apoptotic response to stress and abnormal cell cycle-related gene expression. Importantly, NBS neural progenitor cells (NBS-NPCs) show down-regulation of neural developmental genes, which seems to be mediated by P53. Our results demonstrate the importance of NBS1 in early human development, shed new light on the molecular mechanisms underlying this severe syndrome and further expand our knowledge of the genomic stress cells experience during the reprogramming process.

ORGANISM(S): Homo sapiens

PROVIDER: GSE83686 | GEO | 2016/07/19

SECONDARY ACCESSION(S): PRJNA329525

REPOSITORIES: GEO

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Chromosomal Instability and Molecular Defects in Induced Pluripotent Stem Cells with Nijmegen Breakage Syndrome

Project description:Nijmegen breakage syndrome (NBS) results from the absence of the NBS1 protein, responsible for detection of DNA double-strand breaks (DSBs). NBS is characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. Here we show successful reprogramming of NBS fibroblasts into induced pluripotent stem cells (NBS-iPSCs). Our data suggest a strong selection for karyotypically normal fibroblasts to go through the reprogramming process. NBS-iPSCs then acquire numerous chromosomal aberrations and show a delayed response to DSB induction. Furthermore, NBS-iPSCs display slower growth, mitotic inhibition, a reduced apoptotic response to stress and abnormal cell cycle-related gene expression. Importantly, NBS neural progenitor cells (NBS-NPCs) show down-regulation of neural developmental genes, which seems to be mediated by P53. Our results demonstrate the importance of NBS1 in early human development, shed new light on the molecular mechanisms underlying this severe syndrome and further expand our knowledge of the genomic stress cells experience during the reprogramming process. Gene expression analysis was performed on a total of 6 human cell lines, including WT and NBS Neural progenitor cells (NPCs) and NBS-iPSCs

2016-07-19 | E-GEOD-83686 | biostudies-arrayexpress

iPSCs from patients with NBS as a model uncovering disease mechanisms and a screening platform for anti-oxidants modifying genomic stability [iPSCs]

Project description:Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive genetic disorder, first described 1981 in Nijmegen, Holland. The characteristics of NBS include genomic instability (resulting in early onset of malignancies), premature aging, microcephaly and other growth retardations, immune deficiency, and impaired puberty and fertility in females. The consequence of these manifestations is a severe decrease in average life span, caused by cancer or infection of the respiratory and urinary tract. We reprogrammed fibroblasts from NBS patients into induced pluripotent stem cells (iPSCS) to bypass premature senescence and to generate an unlimited cell source for modeling purposes. We screened the influence of antioxidants on intracellular levels of ROS and DNA damage and found that EDHB was able to decrease DNA damage in the presence of high oxidative stress. Furthermore, we found that NBS fibroblasts, but not NBS-iPSCs were more susceptible to the induction of DNA damage than their normal counterparts. We performed global transcriptome analysis comparing NBS to normal fibroblasts and NBS-iPSCs to hESCs. There, we found, that TP53 was activated and cell cycle genes broadly down-regulated in NBS fibroblasts and up-regulation of glycolysis specifically in NBS-iPSCs.

2017-08-18 | GSE94707 | GEO

iPSCs from patients with NBS as a model uncovering disease mechanisms and a screening platform for anti-oxidants modifying genomic stability [fibroblasts]

2017-08-18 | GSE94706 | GEO

Heterozygous carriers of Nijmegen Breakage Syndrome Have a Distinct Gene Expression Phenotype.

2006-07-26 | GSE3894 | GEO

Genome-wide expression analysis in murine liver after Nbs1 induced knockout

Project description:NBS1 (Nbn in Mus musculus) is a critical component of the MRN (MRE11/RAD50/NBS1) complex, which regulates ATM- and ATR-mediated DNA damage response (DDR) pathways. NBS1 mutations cause the human genomic instability syndrome Nijmegen Breakage Syndrome (NBS), in which microcephaly and intellectual disability are marked neuronal deficits. NBS1 is essential for life, because of its function in the DDR to ensure proliferation and preventing the cell death of replicating cells. However, the function of NBS1 in postmitotic cells is unclear. To explore the possible role of Nbs1 in non-dividing cells and the effection of its deletion on gene expression, RNA-seq was carried out with Nbs1 induced knockout liver samples, in which most cells are postmitotic.

2022-09-16 | GSE137505 | GEO

Genome-wide expression analysis in murine brain in E14.5 vs. 10.5m old mice

Project description:NBS1 (Nbn in Mus musculus) is a critical component of the MRN (MRE11/RAD50/NBS1) complex, which regulates ATM- and ATR-mediated DNA damage response (DDR) pathways. NBS1 mutations cause the human genomic instability syndrome Nijmegen Breakage Syndrome (NBS), in which microcephaly and intellectual disability are marked neuronal deficits. NBS1 is essential for life, because of its function in the DDR to ensure proliferation and preventing the cell death of replicating cells. However, the function of NBS1 in postmitotic cells is unclear. To explore the possible role of Nbs1 in non-dividing cells and the effection of its deletion on gene expression, RNA-seq was carried out to compare the expression of Nbs1 and other DDR molecules in developing and adult brain.

2020-08-20 | GSE137506 | GEO

Chromosomal instability associated with adverse outcome: a case report of patient with Nijmegen breakage syndrome and rapidly developed T-NHL with complex karyotype

Project description:Nijmegen breakage syndrome (NBS) is a rare genetic disorder inherited in an autosomal recessive pattern associated with an increased risk of developing lymphoproliferative disorders, mainly non-Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL). This work presents a patient previously diagnosed with Nijmegen breakage syndrome who rapidly developed T-NHL despite of constant medical supervision. Cytogenetic karyotype and microarray tests revealed complex aberrations, indicating enhanced chromosomal instability.

2020-04-07 | GSE148229 | GEO

Transcription profiling of human heterozygous carriers of Nijmegen Breakage Syndrome reveals distinct gene expression phenotype.

Project description:By comparing the expression levels of genes between carriers of Nijmegen Breakage Syndrome and non-carriers, we showed that NBS carriers have a distinct gene expression phenotype. Experiment Overall Design: Gene expression analysis using Affymetrix Human Focus arrays; comparison of expression levels of genes using t-statistic and identification of genes that allow classification of individuals as carriers or non-carriers by linear discriminant analysis.

2008-06-12 | E-GEOD-3894 | biostudies-arrayexpress

NF-κB activation impairs somatic cell reprogramming in ageing [NGPS_iPSCs]

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.

2015-07-01 | E-GEOD-65170 | biostudies-arrayexpress

On-chip neural induction boosts neural stem cell commitment: toward a pipeline for iPSC-based therapies

Project description:The clinical translation of induced pluripotent stem cells (iPSCs) holds great potential for personalized therapeutics. However, the current workflow to generate iPSCs is expensive, time-consuming, and requires standardization. We present a simplified microfluidic approach for reprogramming fibroblasts into iPSCs and their subsequent differentiation into neural stem cells (NSCs). Our method exploits microphysiological technology, providing a 100-fold reduction in reagents for reprogramming and a 9-fold reduction in number of input cells. The iPSCs generated from microfluidic reprogramming of fibroblasts show upregulation of pluripotency markers and downregulation of fibroblast markers, on par with those reprogrammed in the standardized well-conditions. The NSCs differentiated in microfluidic chips show upregulation of neuroectodermal markers (ZIC1, PAX6, SOX1), highlighting their propensity for nervous system development. We then compare the cells obtained on conventional well plates and microfluidic chips for reprogramming and neural induction by bulk RNA sequencing. Pathway enrichment analysis of NSCs generated in the chip showed neural stem cell development enrichment and boosted commitment to the neural stem cell lineage in the initial phases of neural induction, attributed to the confined environment in a microfluidic chip. This method provides a cost-effective pipeline to reprogram and differentiate iPSCs which can be made compliant with the current good manufacturing practices for therapeutics.

2024-04-08 | GSE255748 | GEO

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