Mesenchymal stem cells derived from patients with premature ageing syndromes display hallmarks of physiological ageing
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ABSTRACT:
PROVIDER: PRJNA835736 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19118005_1.fastq.gz | Fastqsanger.gz | |||
| SRR19118005_2.fastq.gz | Fastqsanger.gz | |||
| SRR19118006_1.fastq.gz | Fastqsanger.gz | |||
| SRR19118006_2.fastq.gz | Fastqsanger.gz | |||
| SRR19118007_1.fastq.gz | Fastqsanger.gz |
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Project description:Mesenchymal stem cells derived from patients with premature ageing syndromes display hallmarks of physiological ageing [array]
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Project description:Mesenchymal stem cells derived from patients with premature ageing syndromes display hallmarks of physiological ageing [RNA-Seq]
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Project description:Progeroid syndromes are rare genetic diseases with a majority of autosomal dominant transmission, the prevalence of which is less than 1 / 10,000,000. These syndromes caused by mutations in the LMNA gene encoding A-type Lamins belong to the group of disorders called laminopathies. Lamins are implicated in the architecture and function of the nucleus and chromatin. Patients affected with progeroid laminopathies display accelerated ageing of mesenchymal stem cells (MSCs)-derived tissues associated with nuclear morphological abnormalities. In order to identify pathways altered in progeroid patients’ MSCs, we used induced pluripotent stem cells (hiPSCs) from patients affected with classical Hutchinson-Gilford Progeria Syndrome (HGPS, c.1824C>T - p.G608G), HGPS-Like Syndrome (HGPS-L; c.1868C>G - p.T623S) associated with farnesylated prelamin A accumulation, or Atypical Progeroid Syndromes (APS; homozygous c.1583C> T - p.T528M; heterozygous c.1762T>C - p.C588R; compound heterozygous c.1583C>T and c.1619T>C - p.T528M and p.M540T) without progerin accumulation. By comparative analysis of the transcriptome and methylome of hiPSC-derived MSCs, we found that patient’s MSCs display specific DNA methylation patterns and modulated transcription at early stages of differentiation. We further explored selected biological processes deregulated in the presence of LMNA variants and confirmed alterations of age-related pathways during MSC differentiation. In particular, we report the presence of an altered mitochondrial pattern, an increased response to double-strand DNA damage and telomere erosion in HGPS, HGPS-L and APS MSCs, suggesting converging pathways, independent of progerin accumulation, but a distinct DNA methylation profile in HGPS and HGPS-L compared to APS cells.
2022-09-12 | GSE202368 | GEO
Project description:Progeroid syndromes are rare genetic diseases with a majority of autosomal dominant transmission, the prevalence of which is less than 1 / 10,000,000. These syndromes caused by mutations in the LMNA gene encoding A-type Lamins belong to the group of disorders called laminopathies. Lamins are implicated in the architecture and function of the nucleus and chromatin. Patients affected with progeroid laminopathies display accelerated ageing of mesenchymal stem cells (MSCs)-derived tissues associated with nuclear morphological abnormalities. In order to identify pathways altered in progeroid patients’ MSCs, we used induced pluripotent stem cells (hiPSCs) from patients affected with classical Hutchinson-Gilford Progeria Syndrome (HGPS, c.1824C>T - p.G608G), HGPS-Like Syndrome (HGPS-L; c.1868C>G - p.T623S) associated with farnesylated prelamin A accumulation, or Atypical Progeroid Syndromes (APS; homozygous c.1583C> T - p.T528M; heterozygous c.1762T>C - p.C588R; compound heterozygous c.1583C>T and c.1619T>C - p.T528M and p.M540T) without progerin accumulation. By comparative analysis of the transcriptome and methylome of hiPSC-derived MSCs, we found that patient’s MSCs display specific DNA methylation patterns and modulated transcription at early stages of differentiation. We further explored selected biological processes deregulated in the presence of LMNA variants and confirmed alterations of age-related pathways during MSC differentiation. In particular, we report the presence of an altered mitochondrial pattern, an increased response to double-strand DNA damage and telomere erosion in HGPS, HGPS-L and APS MSCs, suggesting converging pathways, independent of progerin accumulation, but a distinct DNA methylation profile in HGPS and HGPS-L compared to APS cells.
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Project description:Progeroid syndromes are rare genetic diseases with most of autosomal dominant transmission, the prevalence of which is less than 1/10,000,000. These syndromes caused by mutations in the <i>LMNA</i> gene encoding A-type lamins belong to a group of disorders called laminopathies. Lamins are implicated in the architecture and function of the nucleus and chromatin. Patients affected with progeroid laminopathies display accelerated aging of mesenchymal stem cells (MSCs)-derived tissues associated with nuclear morphological abnormalities. To identify pathways altered in progeroid patients' MSCs, we used induced pluripotent stem cells (hiPSCs) from patients affected with classical Hutchinson-Gilford progeria syndrome (HGPS, c.1824C&gt;T-p.G608G), HGPS-like syndrome (HGPS-L; c.1868C&gt;G-p.T623S) associated with farnesylated prelamin A accumulation, or atypical progeroid syndromes (APS; homozygous c.1583C&gt; T-p.T528M; heterozygous c.1762T&gt;C-p.C588R; compound heterozygous c.1583C&gt;T and c.1619T&gt;C-p.T528M and p.M540T) without progerin accumulation. By comparative analysis of the transcriptome and methylome of hiPSC-derived MSCs, we found that patient's MSCs display specific DNA methylation patterns and modulated transcription at early stages of differentiation. We further explored selected biological processes deregulated in the presence of <i>LMNA</i> variants and confirmed alterations of age-related pathways during MSC differentiation. In particular, we report the presence of an altered mitochondrial pattern; an increased response to double-strand DNA damage; and telomere erosion in HGPS, HGPS-L, and APS MSCs, suggesting converging pathways, independent of progerin accumulation, but a distinct DNA methylation profile in HGPS and HGPS-L compared with APS cells.
| S-EPMC9475049 | biostudies-literature
Project description:Premature-ageing syndromes are a heterogeneous group of rare genetic disorders resembling features of accelerated ageing and resulting from mutations in genes coding for proteins required for nuclear lamina architecture, DNA repair and maintenance of genome stability, mitochondrial function and other cellular processes. Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best-characterized progeroid syndromes referred to as childhood- and adulthood-progeria, respectively. This article provides an updated overview of the mutations leading to HGPS, WS, and to the spectrum of premature-ageing laminopathies ranging in severity from congenital restrictive dermopathy (RD) to adult-onset atypical WS, including RD-like laminopathies, typical and atypical HGPS, more and less severe forms of mandibuloacral dysplasia (MAD), Néstor-Guillermo progeria syndrome (NGPS), atypical WS, and atypical progeroid syndromes resembling features of HGPS and/or MAD but resulting from impaired DNA repair or mitochondrial functions, including mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome and mandibuloacral dysplasia associated to MTX2 (MADaM). The overlapping signs and symptoms among different premature-ageing syndromes, resulting from both a large genetic heterogeneity and shared pathological pathways underlying these conditions, require an expert clinical evaluation in specialized centers paralleled by next-generation sequencing of panels of genes involved in these disorders in order to establish as early as possible an accurate clinical and molecular diagnosis for a proper patient management.
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Project description:Impaired CHD6 function links misregulation of autophagy and DNA damage response to premature ageing
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Project description:The breach of proteostasis, leading to the accumulation of protein aggregates, is a hallmark of ageing and age-associated disorders, up to now well-established in neurodegeneration. Few studies have addressed the issue of dysfunctional cell response to protein deposition also for the cardiovascular system. However, the molecular basis of proteostasis decline in vascular cells, as well as its relation to ageing, are not understood. Recent studies have indicated the associations of Nrf2 transcription factor, the critical modulator of cellular stress-response, with ageing and premature senescence. In this report, we outline the significance of protein aggregation in physiological and premature ageing of murine and human endothelial cells (ECs). Our study shows that aged donor-derived and prematurely senescent Nrf2-deficient primary human ECs, but not those overexpressing dominant-negative Nrf2, exhibit increased accumulation of protein aggregates. Such phenotype is also found in the aortas of aged mice and young Nrf2 tKO mice. Ageing-related loss of proteostasis in ECs depends on Keap1, well-known repressor of Nrf2, recently perceived as a key independent regulator of EC function. Ageing-induced deposition of protein aggregates in ECs is associated with impaired autophagy and can be counteracted by Keap1 depletion or rapamycin treatment. Our results show that Keap1:Nrf2 protein balance predominates Nrf2 transcription-dependent mechanisms in governing proteostasis and ageing in ECs.
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Project description:Dyskeratosis congenita (DKC) and idiopathic aplastic anemia (AA) are bone marrow failure syndromes that share characteristics of premature aging with severe telomere attrition. In this study, we analyzed blood samples of 62 AA and 13 DKC patients to demonstrate that their epigenetic age predictions are overall increased, albeit not directly correlated with telomere length. Aberrant DNA methylation was observed in the gene PRDM8 in DKC and AA as well as in other diseases with premature aging phenotype, such as Down syndrome, Werner syndrome and Hutchinson-Gilford-Progeria syndrome. To gain further insight into the functional relevance of PRDM8 we generated induced pluripotent stem cells (iPSCs) with heterozygous and homozygous knockout. Loss of PRDM8 impaired hematopoietic and neuronal differentiation of iPSCs, but it did not impact on epigenetic age. Taken together, aberrant DNA methylation in PRDM8 provides a biomarker for bone marrow failure syndromes, which may contribute to the hematopoietic and neuronal phenotypes of premature aging syndromes.
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