DNA methylation in progeroid syndromes
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ABSTRACT:
PROVIDER: PRJNA544684 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Constitutive heterochromatin is responsible for genome repression of DNA enriched in repetitive sequences, telomeres, and centromeres. In higher eukaryotes, constitutive heterochromatin is mostly segregated at the nuclear periphery, where the interaction with the nuclear lamina makes the genome more resistant to transcription. During physiological and pathological premature aging, heterochromatin homeostasis is profoundly compromised. Here we show that LINE-1 (L1) RNA accumulation is an early event in both typical and atypical progeroid syndromes. Depletion of L1 RNA in cells from different progeroid syndrome patients using specific antisense oligonucleotides (ASO) restores the levels of heterochromatin epigenetic marks, reverses DNA methylation age and counteracts the expression of senescence-associated genes. Moreover, proteome profiling involved in senescence phenotype was partially restored upon depletion of LINE-1 RNA in both Hutchinson-Gilford Progeria Syndrome (HGPS) and Werner syndrome (WRN-/-).
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Project description:Genome-wide DNA methylation profiling of patients with WRN, LMNA or POLD1 mutations
2019-06-07 | GSE131752 | GEO
Project description:Progeroid syndromes are rare genetic disorders that phenotypically resemble natural aging. Despite identification of causal mutations, mechanisms that generate their clinical manifestations remain elusive. Here, we identified a DNA replication timing (RT) signature that distinguishes progeroid syndromes from normal aging and identifies TP63 gene as a new disease marker. Abnormal TP63 RT appears early during differentiation of progeroid iPSCs and is associated with altered gene variant expression. Our findings demonstrate the utility of RT signatures to identify novel biomarkers not detected by other methods, reveal abnormal TP63 RT as an early event in progeroid disease progression and offer TP63 gene regulation as a potential therapeutic target.
2017-11-16 | GSE98472 | GEO
Project description:Progeroid syndromes are rare genetic disorders that phenotypically resemble natural aging. Despite identification of causal mutations, mechanisms that generate their clinical manifestations remain elusive. Here, we identified a DNA replication timing (RT) signature that distinguishes progeroid syndromes from normal aging and identifies TP63 gene as a new disease marker. Abnormal TP63 RT appears early during differentiation of progeroid iPSCs and is associated with altered gene variant expression. Our findings demonstrate the utility of RT signatures to identify novel biomarkers not detected by other methods, reveal abnormal TP63 RT as an early event in progeroid disease progression and offer TP63 gene regulation as a potential therapeutic target.
2017-11-16 | GSE98471 | 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.
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.
2022-09-12 | GSE202364 | GEO
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.
2020-08-31 | GSE141106 | GEO
Project description:DNA repair-deficient Ercc1Δ/- mice show premature cell death, senescence and numerous accelerated aging features limiting lifespan to 4-6 month. Simultaneously they exhibit a ‘survival response’, which suppresses growth and enhances maintenance, resembling the anti-aging response induced by dietary restriction (DR). Here we report that subjecting these progeroid, dwarf mutants to actual dietary restriction (DR) resulted in the largest lifespan increase recorded in mammals. Thirty percent DR tripled median and maximal remaining lifespan, and drastically retarded numerous aspects of accelerated aging, e.g. DR animals retained 50% more neurons and maintained full motoric function. The DR response in Ercc1Δ/- mice resembled DR in wild type animals including reduced insulin signaling. Interestingly, ad libitum Ercc1Δ/- liver expression profiles showed preferential extinction of expression of long genes, consistent with genome-wide accumulation of stochastic, transcription-blocking lesions, which affect long genes more than short ones. DR largely prevented this decline of transcriptional output, indicating that DR prolongs genome function. Our findings strengthen the link between DNA damage and aging, establish Ercc1Δ/- mice as powerful model for identifying interventions to promote healthy aging, reveal untapped potential for reducing endogenous damage, provide new venues for understanding the molecular mechanism of DR, and suggest a counterintuitive DR-like therapy for human progeroid genome instability syndromes and DR-like interventions for preventing neurodegenerative diseases.
2016-09-09 | GSE77226 | GEO
Project description:Genome wide DNA methylation profiling of 12 control and 15 progeroid laminopahties samples. The Infinium MethylationEPIC Kit was used to measure DNA methylation across approximately 868,564 CpG sites.
2022-02-15 | GSE182991 | GEO
Project description:DNA Methylation Identifies Genetically and Prognostically Distinct Subtypes of Myelodysplastic Syndromes
| PRJNA532913 | ENA