DNA Methylation Variations and Epigenetic Aging in Telomere Biology Disorders
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE224847 | GEO | 2023/05/10
REPOSITORIES: GEO
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Project description:Clonal hematopoiesis (CH) in inherited bone marrow failure (BMF) is disease-specific but has been poorly characterized in telomere biology disorders (TBD).We studied the architecture, trajectories, and impact of CH in a cohort of 207 TBD patients and assessed the clinical relevance of molecular signatures linked to telomere dysfunction. Most patients (92%) had known germline mutations in TBD genes. CH was rare in asymptomatic but present in 46% of symptomatic patients, recurrently in PPM1D, POT1, TERT promoter (TERTp), and U2AF1. CH frequency increased with age and was significantly higher than in age- matched controls. CH in PPM1D/TERTp was enriched in TERT patients while CH in POT1 was enriched in TINF2 patients. CH in myelodysplastic syndromes (MDS)-related genes, most commonly splicing factors, was enriched in TERT/TERC patients. CH in TERTp, TP53 ̧ and MDS- related genes associated with poorer survival. Chromosome 1q (Chr1q) gain, and splicing factor gene (dominated by U2AF1S34/Q157R) or TP53 mutations increased the risk of MDS/acute myeloid leukemia (AML) development, regardless of allele burden. Trajectories with successive acquisition of MDS-related CH driven by U2AF1S34/Q157R were maladaptive, while adaptive CH involved branched POT1/PPM1D/TERTp trajectories. U2AF1S34/Q157R compensated aberrant TP53 and interferon-γ pathway activation that contribute to hematopoietic stem cell exhaustion in TBD.
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Project description:Dyskeratosis congenita (DC) is an inherited multi-system disorder, characterized by oral leukoplakia, nail dystrophy, and abnormal skin pigmentation, as well as high rates of bone marrow failure, solid tumors, and other medical problems such as osteopenia. DC and telomere biology disorders (collectively referred to as TBD here) are caused by germline mutations in telomere biology genes leading to very short telomeres and limited proliferative potential of hematopoietic stem cells. We found that skeletal stem cells (SSCs) within the bone marrow stromal cell population (BMSCs, also known as bone marrow-derived mesenchymal stem cells), may contribute to the hematological phenotype. TBD-BMSCs exhibited reduced clonogenicity, reduced telomerase activity, spontaneous differentiation into adipocytes and fibrotic cells, and increased senescence in vitro. Upon in vivo transplantation into mice, TBD-BMSCs failed to form bone or support hematopoiesis, unlike normal BMSCs. TERC reduction (a TBD-associated gene) in normal BMSCs by siTERC-RNA recapitulated the TBD-BMSC phenotype by reducing proliferation and secondary colony forming efficiency, and by accelerating senescence in vitro. Microarray profiles of control and siTERC-BMSCs showed decreased hematopoietic factors at the mRNA level, and decreased secretion of factors at the protein level. These findings are consistent with defects in SSCs/BMSCs contributing to bone marrow failure in TBD.
2014-12-09 | GSE64023 | GEO
Project description:Dyskeratosis congenita (DC) is an inherited multi-system disorder, characterized by oral leukoplakia, nail dystrophy, and abnormal skin pigmentation, as well as high rates of bone marrow failure, solid tumors, and other medical problems such as osteopenia. DC and telomere biology disorders (collectively referred to as TBD here) are caused by germline mutations in telomere biology genes leading to very short telomeres and limited proliferative potential of hematopoietic stem cells. We found that skeletal stem cells (SSCs) within the bone marrow stromal cell population (BMSCs, also known as bone marrow-derived mesenchymal stem cells), may contribute to the hematological phenotype. TBD-BMSCs exhibited reduced clonogenicity, reduced telomerase activity, spontaneous differentiation into adipocytes and fibrotic cells, and increased senescence in vitro. Upon in vivo transplantation into mice, TBD-BMSCs failed to form bone or support hematopoiesis, unlike normal BMSCs. TERC reduction (a TBD-associated gene) in normal BMSCs by siTERC-RNA recapitulated the TBD-BMSC phenotype by reducing proliferation and secondary colony forming efficiency, and by accelerating senescence in vitro. Microarray profiles of control and siTERC-BMSCs showed decreased hematopoietic factors at the mRNA level, and decreased secretion of factors at the protein level. These findings are consistent with defects in SSCs/BMSCs contributing to bone marrow failure in TBD. RNA (5 mg) isolated from N-BMSCs, siNC-BMSCs and siTERC-BMSCs 72hrs after transfection using an RNeasy Mini kit (Qiagen), was reverse transcribed and hybridized to an Affymetrix GeneChip Human Genome U133 Plus 2.0 array (LMT, NCI-Frederick). Three independent replicates for each experimental condition were carried out to control for intra-sample variation. Genes that were under/over-represented by >2-fold were analyzed using GeneSpring software. Signal intensity values were normalized using RMA (Robust Multi-array Analysis) summarization and baseline transformation to median of all samples was performed. Entities were filtered based on their signal intensity values. Hierarchical clustering was performed on filtered signal intensity (>20.0), non-averaged, fold change >2. A fold change analysis (>10-fold) was performed to generate a list of top genes under/over represented between the groups.
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Project description:DNA Methylation Variations and Epigenetic Aging in Telomere Biology Disorders
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Project description:Genome wide DNA methylation assays was conducted using the Illumina Infinium MethylationEPIC BeadArray technology (Methyl850K chip) that allows genome-wide DNA methylation analysis of 866,836 CpG sites. We included baseline and 2-year follow-up samples from 25 persons with mild cognitive impairment (cases) and 20 persons with cognitively normal (controls). Sample was balanced by age and sex.
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Project description:Telomere Biology Disorders (TBDs) are characterized by mutations in telomere-related genes leading to short telomeres and premature aging but with no strict correlation between telomere length and disease severity. Epigenetic alterations are also markers of aging and we aimed to evaluate whether DNA methylation (DNAm) could be part of the pathogenesis of TBDs. In blood from 35 TBD cases, genome-wide DNAm were analyzed and the cases were grouped based on relative telomere length (RTL): short (S), with RTL close to normal controls, and extremely short (ES). TBD cases had increased epigenetic age and DNAm alterations were most prominent in the ES-RTL group. Thus, the differentially methylated (DM) CpG sites could be markers of short telomeres but could also be one of the mechanisms contributing to disease phenotype since DNAm alterations were observed in symptomatic, but not asymptomatic, cases with S-RTL. Furthermore, two or more DM-CpGs were identified in four genes previously linked to TBD or telomere length (PRDM8, SMC4, VARS, and WNT6) and in three genes that were novel in telomere biology (MAS1L, NAV2, and TM4FS1). The DM-CpGs in these genes could be markers of aging in hematological cells, but they could also be of relevance for the progression of TBD.
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Project description:Genomo wide DNA methylation analysis of isolated pancreatic exocrine cells from high fat dietary and normal dietary mice. The illumima Infinium MethylationEPIC was used to obtain DNA methylatoin profiles across approximately 287K CpGs in isolated cultured cells. Total twelve samples (seven controls and five obese cases) were included in the file.
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