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Arterial stiffness and cardiac dysfunction in Hutchinson-Gilford Progeria Syndrome corrected by inhibition of Lysyl Oxidase

ABSTRACT: Arterial stiffness and cardiac dysfunction in Hutchinson-Gilford Progeria Syndrome corrected by inhibition of Lysyl Oxidase

PROVIDER: PRJNA694470 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13517660_1.fastq.gz	Fastqsanger.gz
	SRR13517660_2.fastq.gz	Fastqsanger.gz
	SRR13517661_1.fastq.gz	Fastqsanger.gz
	SRR13517661_2.fastq.gz	Fastqsanger.gz
	SRR13517662_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Arterial stiffness and cardiac dysfunction in Hutchinson-Gilford Progeria Syndrome corrected by inhibition of Lysyl Oxidase

Project description:Purpose: Arterial stiffening is a hallmark of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), but the molecular regulators remain unknown. Here, we show that the LMNAG609G mouse model of HGPS recapitulates the premature arterial stiffening seen in human HGPS. To gain a better understanding of potential stiffness-regulators in LMNAG609G mice, we performed RNA-sequencing analysis on cleaned descending aortas from 2- and 24-month WT and 2-month LMNAG609G mice on a C57BL6 background. Methods: Descending aortas containing the intimal, medial and adventitial layers were isolated from 2- and 24-month male WT and 2-month HGPS mice, and RNA was extracted using the RNeasy Plus Micro kit (Qiagen 74034). The high-throughput library was prepared using the TruSeq stranded total RNA (ribo-Zero) kit (Illumina 20037135). Paired-end sequencing was performed on a HiSeq4000 Sequencing System (Illumina) and generated 14-30 million reads/sample.

2021-02-09 | GSE165409 | GEO

Project description:This SuperSeries is composed of the following subset Series: GSE41751: Correlated alterations in genome organization, histone methylation, and DNA-lamina interactions in Hutchinson-Gilford progeria syndrome (expression) GSE41757: Correlated alterations in genome organization, histone methylation, and DNA-lamina interactions in Hutchinson-Gilford progeria syndrome (ChIP-seq) GSE41763: Correlated alterations in genome organization, histone methylation, and DNA-lamina interactions in Hutchinson-Gilford progeria syndrome (Hi-C) Refer to individual Series

2012-10-30 | E-GEOD-41764 | biostudies-arrayexpress

Endothelial-to-mesenchymal transition contributes to accelerated atherosclerosis in Hutchinson–Gilford progeria syndrome

Project description:The main goal of this study was to gain insight into the mechanisms underlying phenotypic changes in endothelial cells during atherosclerosis associated with Hutchinson-Gilford progeria syndrome, a premature aging syndrome. To this end, we performed an RNAseq experiment with aortic intima samples from atheroprone mice with ubiquitous and VSMC-specific progeria expression and their corresponding controls.

2024-06-05 | GSE269166 | GEO

Single-Dose CRISPR/Cas9 Therapy Extends Lifespan of Mice with Hutchinson-Gilford Progeria Syndrome

Project description:Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare lethal genetic disorder characterized with symptoms reminiscent of accelerated aging. The major underlying genetic cause is a substitution mutation in the gene coding for lamin A, causing the production of a toxic isoform called progerin. Here we show the RNA sequencing analyses performed on primary mouse fibroblasts of different genotypes (in terms of Progeria; Cas9 background) treated with Cas9 guide RNAs targeting Lmna/Progerin. The mouse genetic background in (1) Pro/Pro;Cas9/+: homozygous for Progeria and heterozygous for transgenic Cas9 The mouse genetic background in (2) Pro/+; +/+: heterozygous for Progeria and no transgenic Cas9 (wild type) The mouse genetic background in (3) +/+;Cas9/+: no Progeria (wild type) and heterozygous for transgenic Cas9

2019-02-15 | GSE122865 | 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

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

Arterial stiffness and cardiac dysfunction in Hutchinson-Gilford Progeria Syndrome corrected by inhibition of lysyl oxidase.

Project description:Arterial stiffening and cardiac dysfunction are hallmarks of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), but the molecular regulators remain unknown. Here, we show that the LaminAG609G mouse model of HGPS recapitulates the premature arterial stiffening and early diastolic dysfunction seen in human HGPS. Lysyl oxidase (LOX) is up-regulated in the arteries of these mice, and treatment with the LOX inhibitor, β-aminopropionitrile, improves arterial mechanics and cardiac function. Genome-wide and mechanistic analysis revealed reduced expression of the LOX-regulator, miR-145, in HGPS arteries, and forced expression of miR-145 restores normal LOX gene expression in HGPS smooth muscle cells. LOX abundance is also increased in the carotid arteries of aged wild-type mice, but its spatial expression differs from HGPS and its up-regulation is independent of changes in miR-145 abundance. Our results show that miR-145 is selectively misregulated in HGPS and that the consequent up-regulation of LOX is causal for premature arterial stiffening and cardiac dysfunction.

| S-EPMC8008950 | biostudies-literature

Comparison of Hutchinson–Gilford Progeria Syndrome fibroblast cell lines to control fibroblast cell lines

Project description:Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disease with widespread phenotypic features resembling premature aging. HGPS was recently shown to be caused by dominant mutations in the LMNA gene, resulting in the in-frame deletion of 50 amino acids near the carboxyl terminus of the encoded lamin A protein. Children with this disease typically succumb to myocardial infarction or stroke caused by severe atherosclerosis at an average age of 13 years. To elucidate further the molecular pathogenesis of this disease, we compared the gene expression patterns of three HGPS fibroblast cell lines heterozygous for the LMNA mutation with three normal, age-matched cell lines. We defined a set of 361 genes (1.1% of the approximately 33 000 genes analyzed) that showed at least a 2-fold, statistically significant change. The most prominent categories encode transcription factors and extracellular matrix proteins, many of which are known to function in the tissues severely affected in HGPS. The most affected gene, MEOX2/GAX, is a homeobox transcription factor implicated as a negative regulator of mesodermal tissue proliferation. Thus, at the gene expression level, HGPS shows the hallmarks of a developmental disorder affecting mesodermal and mesenchymal cell lineages. The identification of a large number of genes implicated in atherosclerosis is especially valuable, because it provides clues to pathological processes that can now be investigated in HGPS patients or animal models. Keywords: microarrays, Hutchinson–Gilford progeria syndrome, HGPS

2005-12-31 | GSE3860 | GEO

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

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.

2020-01-02 | GSE84356 | GEO

Transcription profiling of primary fibroblasts from a family with autosomal recessive Hutchinson-Gilford Progeria Syndrome

Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disorder displaying features reminiscent of premature senescence caused by germline mutations in the LMNA gene encoding lamin A and C, essential components of the nuclear lamina. By studying a family with homozygous LMNA mutation (K542N), we showed that HGPS can also be caused by mutations affecting both isoforms, lamin A and C (J Med Genet 2004;41:609M-^V614). With the aim to elucidate the molecular mechanisms underlying the pathogenesis of lamin A/C-related (hereditary) HGPS, we investigated primary cultured skin fibroblasts from affected homozygous K542N carriers (n=3), healthy heterozygotes (n=3), and controls (n=3) for differences in global gene expression using GeneChip Human Genome U133 Plus 2.0 arrays (Affymetrix UK Ltd.).

2011-06-27 | E-MEXP-3097 | biostudies-arrayexpress

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