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Correlated alterations in genome organization, histone methylation, and DNA-lamina interactions in Hutchinson-Gilford progeria syndrome (ChIP-seq)

ABSTRACT: Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease that is frequently caused by a de novo point mutation at position 1824 in LMNA. This mutation activates a cryptic splice donor site in exon 11, and leads to an in-frame deletion within the prelamin A mRNA and the production of a dominant negative lamin A protein, known as progerin. Here we show that HGPS cells experience genome-wide alterations in patterns of H3K27me3 deposition, changes in the associations of genomic loci with nuclear lamin A/C, and, at late passages, genome-wide loss of spatial compartmentalization of active and inactive chromatin domains that characterizes chromosome folding in normal cells. We further demonstrate that the H3K27me3 changes associate with gene expression alterations in HGPS cells. Our results support a model that the accumulation of progerin in the nuclear lamina leads to altered H3K27me3 marks in heterochromatin, possibly through the down-regulation of EZH2, and disrupts heterochromatin-lamina interactions. These changes may then lead to the genomic disorganization and changes in transcriptional regulation we observe in HGPS fibroblasts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE41757 | GEO | 2012/10/30

SECONDARY ACCESSION(S): PRJNA178125

REPOSITORIES: GEO

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Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease that is frequently caused by a de novo point mutation at position 1824 in LMNA. This mutation activates a cryptic splice donor site in exon 11, and leads to an in-frame deletion within the prelamin A mRNA and the production of a dominant negative lamin A protein, known as progerin. Here we show that HGPS cells experience genome-wide alterations in patterns of H3K27me3 deposition, changes in the associations of genomic loci with nuclear lamin A/C, and, at late passages, genome-wide loss of spatial compartmentalization of active and inactive chromatin domains that characterizes chromosome folding in normal cells. We further demonstrate that the H3K27me3 changes associate with gene expression alterations in HGPS cells. Our results support a model that the accumulation of progerin in the nuclear lamina leads to altered H3K27me3 marks in heterochromatin, possibly through the down-regulation of EZH2, and disrupts heterochromatin-lamina interactions. These changes may then lead to the genomic disorganization and changes in transcriptional regulation we observe in HGPS fibroblasts. ChIP-Seq was performed for H3K27me3 and lamin A/C in the human genome in three primary fibroblast cell lines: an HGPS patient (HGPS), normal cells from the father of the HGPS patient (Father), and age-matched normal cells (Age Control). Two biological replicates were performed.

2012-10-30 | E-GEOD-41757 | biostudies-arrayexpress

Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease that is frequently caused by a de novo point mutation at position 1824 in LMNA. This mutation activates a cryptic splice donor site in exon 11, and leads to an in-frame deletion within the prelamin A mRNA and the production of a dominant negative lamin A protein, known as progerin. Here we show that HGPS cells experience genome-wide alterations in patterns of H3K27me3 deposition, changes in the associations of genomic loci with nuclear lamin A/C, and, at late passages, genome-wide loss of spatial compartmentalization of active and inactive chromatin domains that characterizes chromosome folding in normal cells. We further demonstrate that the H3K27me3 changes associate with gene expression alterations in HGPS cells. Our results support a model that the accumulation of progerin in the nuclear lamina leads to altered H3K27me3 marks in heterochromatin, possibly through the down-regulation of EZH2, and disrupts heterochromatin-lamina interactions. These changes may then lead to the genomic disorganization and changes in transcriptional regulation we observe in HGPS fibroblasts. Hi-C was performed on three primary fibroblast cell lines: an HGPS patient (passage 17 and 19; HGPS), normal cells from the father of the HGPS patient (passage 18; Father), and age-matched normal cells (passage 20; Age Control).

2012-10-30 | E-GEOD-41763 | biostudies-arrayexpress

Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease that is frequently caused by a de novo point mutation at position 1824 in LMNA. This mutation activates a cryptic splice donor site in exon 11, and leads to an in-frame deletion within the prelamin A mRNA and the production of a dominant negative lamin A protein, known as progerin. Here we show that HGPS cells experience genome-wide alterations in patterns of H3K27me3 deposition, changes in the associations of genomic loci with nuclear lamin A/C, and, at late passages, genome-wide loss of spatial compartmentalization of active and inactive chromatin domains that characterizes chromosome folding in normal cells. We further demonstrate that the H3K27me3 changes associate with gene expression alterations in HGPS cells. Our results support a model that the accumulation of progerin in the nuclear lamina leads to altered H3K27me3 marks in heterochromatin, possibly through the down-regulation of EZH2, and disrupts heterochromatin-lamina interactions. These changes may then lead to the genomic disorganization and changes in transcriptional regulation we observe in HGPS fibroblasts. We analyzed gene expression of primary fibroblasts of a Hutchinson-Gilford progeria syndrome patient, a healthy age-matched control, and the patient's healthy father using the Affymetrix GeneChip Human Genome U133 Plus 2.0 Array platform. Arrays were filtered and normalized using RMA. Two replicates were performed.

2012-10-30 | E-GEOD-41751 | biostudies-arrayexpress

2012-10-30 | GSE41751 | GEO

2012-10-30 | GSE41763 | GEO

Reprogramming Hutchinson-Gilford Progeria Syndrome fibroblasts resets epigenomic landscape in patient-derived induced pluripotent stem cells [Affymetrix]

Project description:Hutchinson-Gilford Progeria Syndrome (HGPS) is a segmental premature aging disorder caused by the accumulation of the truncated form of Lamin A known as Progerin within the nuclear lamina. Cellular hallmarks of HGPS include nuclear blebbing, loss of peripheral heterochromatin, defective epigenetic inheritance, altered gene expression, and senescence. To model HGPS using iPSCs, detailed genome-wide and structural analysis of the epigenetic landscape is required to assess the initiation and progression of the disease. We generated a library of iPSC lines from fibroblasts of HGPS patients and controls, including one family trio. Our microarray results suggest that despite the presence of defects associated with Progerin in the nuclear lamina including structural defects, senescence and abnormal epigenetic marks, HGPS fibroblasts can be reprogrammed into iPSCs with transcriptomes that are essentially identical to control iPSCs and hESCs.

2020-01-02 | GSE84351 | GEO

Reprogramming Hutchinson-Gilford Progeria Syndrome fibroblasts resets epigenomic landscape in patient-derived induced pluripotent stem cells [ChIP-Seq]

2020-01-02 | GSE84356 | GEO

Recapitulation of human premature aging by using iPSCs from Hutchinson-Gilford progeria syndrome

Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal human premature aging disease1-5, characterized by premature atherosclerosis and degeneration of vascular smooth muscle cells (SMCs)6-8. HGPS is caused by a single-point mutation in the LMNA gene, resulting in the generation of progerin, a truncated mutant of lamin A. Accumulation of progerin leads to various aging-associated nuclear defects including disorganization of nuclear lamina and loss of heterochromatin9-12. Here, we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts obtained from patients with HGPS. HGPS-iPSCs show absence of progerin, and more importantly, lack the nuclear envelope and epigenetic alterations normally associated with premature aging. Upon differentiation of HGPS-iPSCs, progerin and its associated aging consequences are restored. In particular, directed differentiation of HGPS-iPSCs to SMCs leads to the appearance of premature senescent SMC phenotypes associated with vascular aging. Additionally, our studies identify DNA-dependent protein kinase catalytic subunit (DNAPKcs) as a component of the progerin-containing protein complex. The absence of nuclear DNAPKcs correlates with premature as well as physiological aging. Since progerin also accumulates during physiological aging6,12,13, our results provide an in vitro iPSC-based model with an acceleration progerin accumulation to study the pathogenesis of human premature and physiological vascular aging. Microarray gene expression profiling was done to: (1) Compare differences between WT fibroblasts and fibroblasts from patients suffering of the Hutchinson-Gilford progeria syndrome (2) Check that iPSC originating from WT and patients are in fact similar to ESC

2011-03-14 | E-GEOD-24487 | biostudies-arrayexpress

Recapitulation of human premature aging by using iPSCs from Hutchinson-Gilford progeria syndrome

2011-03-14 | GSE24487 | GEO

Epigenetic deregulation of lamina-associated domains in Hutchinson-Gilford Progeria Syndrome

Project description:Hutchinson-Gilford Progeria Syndrome (HGPS) is a progeroid disease characterized by the early onset of some classically age-related phenotypes including arthritis, loss of body fat and hair and atherosclerosis. Cells from affected individuals express a mutant version of the nuclear envelope protein Lamin A (termed Progerin) and have previously been shown to exhibit prominent chromatin changes. Here, we identify epigenetic deregulation of lamina-associated domains (LADs) as a central feature in the molecular pathology of HGPS. Using ATAC-see/-seq and Infinium MethylationEPIC BeadChip-mediated DNA methylation profiling, we demonstrate that dermal fibroblasts from HGPS patients exhibit both chromatin accessibility and DNA methylation changes that are enriched in LADs. Importantly, we further show that these epigenetic alterations are associated with HGPS-specific gene expression changes. Together, our results establish a central involvement of LADs in the epigenetic deregulation of HGPS and provide novel insight into the molecular changes associated with the disease.

2020-05-07 | GSE149960 | GEO

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