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High throughput sequencing of atypical progeria caused by LMNA R527C mutation

ABSTRACT: High throughput sequencing of atypical progeria caused by LMNA R527C mutation

PROVIDER: PRJNA786245 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17133700_1.fastq.gz	Fastqsanger.gz
	SRR17133700_2.fastq.gz	Fastqsanger.gz
	SRR17133701_1.fastq.gz	Fastqsanger.gz
	SRR17133701_2.fastq.gz	Fastqsanger.gz
	SRR17133702_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Next Generation Sequencing Facilitates Quantitative Analysis of wild type and Lmna R527C mutant mice spleen Transcriptomes with or without 4Gy irradiation.

Project description:To induced the atypical progeria symptoms of LMNA R527C mutant mice, mutant and wild type mice were irradiated at 6 weeks of age with doses of 4 Gy. And to examine the pathologic change of mutant mice, mice were sacrificed at day -1and day 7 post-irradiation and spleen was harvested for RNAseq.

2021-12-07 | GSE190199 | GEO

Genome-wide maps of LADs distribution in control and Dam-WT/Dam-R527C LMNA stabilized Hela cells

Project description:To determine if LMNA R527C mutation affect the arrangement and function of LADs, we performed Lamin A DamID-seq in wild type and mutant LMNA-stablized Hela cells. Reads of Lamin A ChIP-seq in LADs were decreased in mutant cells compared with wild type. These data suggested that the binding affinity of Lamin A to LADs was reduced after R527C mutation

2021-12-07 | GSE190197 | GEO

High throughput sequencing of atypical progeria caused by LMNA R527C mutation

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-12-07 | GSE190200 | GEO

Genome-wide maps of Lamin A-LADs binding affinity in control and LMNA R527C mutant MSCs

Project description:To determine if LMNA R527C mutation affect the arrangement and function of LADs, we performed Lamin A ChIP-seq in wild type and mutant MSCs. Reads of Lamin A ChIP-seq in LADs were decreased in mutant cells compared with wild type. These data suggested that the binding affinity of Lamin A to LADs was reduced after R527C mutation

2021-12-07 | GSE190196 | GEO

Genome-wide maps of chromatin openness in control and LMNA R527C mutant MSCs

Project description:We performed ATAC-seq to examine to chromatin of openness of coding genes in healthy control and LMNA R527C patient-derived MSCs. The reduction of LADs did not increase the accessibility of the promoters flanking coding genes. The genome wide analysis of ATAC-seq showed that openness of coding genes related chromatin was decreased in mutant MSCs.Thus, R527C mutant Lamin A led to dysfunction of LADs and dysregulation of gene transcription, probably, leading to slow down or arrest of cell proliferation and differentiation.

2021-12-07 | GSE190195 | GEO

Chromatin dysfunction facilitates stem cells aging in atypical laminopathy-based progeria Mandibuloacral dysplasia type A (MAD)

Project description:Nuclear lamins orchestrate the nuclear envelope architecture to maintain nuclear homeostasis, such as nuclear integrity and chromatin organization. The LMNA mutations lead to a variety of laminopathies, including progeroid syndrome. Other than typical Hutchinson-Gilford progeria syndrome (HGPS), the mechanism of LMNA mutation associated atypical progeria remains largely unexplored. We used patient-specific induced pluripotent stem cells (iPSCs) and their derivatives to remodel an LMNA (c.1579 C>T, p.R527C) mutation that causes Mandibuloacral dysplasia type A (MAD). Vascular lineages, including vascular smooth muscle cells (VSMCs) and endothelial cells (VECs), exhibited premature ageing phenotypes, such as genome instability and nuclear deformations, whereas neural lineages showed no obvious defects. Based on the observation that MAD-iPSCs derived mesenchymal stem cells (MSCs) also recapitulated accelerated senescence, an integrated multi-omics approach was adapted to reveal the underlying mechanisms of stem cells ageing. We found that among available human MSCs ageing models, MAD-MSCs had the highest transcriptional similarity to normal ageing hMSCs. The nuclear lamina-chromatin interaction was dramatically altered for both A and B type lamin-associating domains (LADs) as well as non-LADs binding sites, resulting in ageing-associated gene dysregulations. Chromatin state analysis further showed increased chromatin accessibility, enhancer remodelling, global chromatin compartments loss, topologically associating domains (TADs) and TAD boundaries reorganization in MAD-MSCs. These hierarchical chromatin reorganizations, coupled with gene dysregulation as consequences, expedited the MAD-MSCs ageing. Collectively, this study revealed a multilevel chromatin dysregulation contributed to ageing significantly in a laminopathy-mediated atypical progeroid syndrome.

2024-10-24 | GSE193694 | GEO

TP53/DNA Damage Response Pathway is Activated and Contributes to the Pathogenesis of Dilated Cardiomyopathy Caused by Lamin A/C Mutations

Project description:To gain insights into the molecular pathogenesis of DCM caused by LMNA mutation, a doxycycline-inducible (Dox-Off) gene expression system was used to express either a wild type (WT) or a mutant LMNA containing the pathogenic variant p.Asp300Asn (LMNAD300N) in cardiac myocytes. The LMNAD300N is associated with DCM in patients with atypical progeroid/Werner syndrome and non-syndromic cardiac progeria. Expression of the mutant LMNAD300N protein in cardiac myocytes led to severe fibrosis, apoptosis, cardiac dysfunction, and premature death. RNA-seq was performed (prior to onset of cardiac dysfunction) to identify gene signatures and transcriptional regulators responsible for this phenotype. Mechanistic studies identified activation of E2F/TP53/DDR, as a major mechanism responsible for the pathogenesis of DCM caused by the LMNAD300N mutation.

2019-04-17 | GSE123916 | 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

Genome-wide maps of chromatin openness in control and LMNA R527C mutant MSCs

Project description:Genome-wide maps of chromatin openness in control and LMNA R527C mutant MSCs

| PRJNA786250 | ENA

Transcription profiling of human Hutchinson-Gilord progeria syndrome fibroblast cell lines with dominant mutation in the LMNA gene and age-matched normal controls

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. Experiment Overall Design: Three fibroblast cell lines derived from HGPS patients were compared to three control fibroblast cell lines using Affymetrix HG-U133A and HG-133B probe arrays. Triplicates were used for each cell line. Total RNA was used in the analysis. Quantitation was done by MAS 5.0 software (Affymetrix).

2007-12-12 | E-GEOD-3860 | biostudies-arrayexpress

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