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SILAC analysis of relative protein abundance in nuclei - PRF168 and PRF167

ABSTRACT: Premature aging disorders provide a lens through which to study the drivers of aging. In Hutchinson-Gilford progeria syndrome (HGPS) a mutant form of the nuclear scaffold protein lamin A distorts nuclei and sequesters nuclear proteins. We used stable isotope labeling and quantitative mass spectrometry to investigate nuclear protein abundance in primary HGPS-derived cells.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Fibroblast

DISEASE(S): Progeria

SUBMITTER: Abby Buchwalter

LAB HEAD: Martin W. Hetzer

PROVIDER: PXD006013 | Pride | 2017-07-07

REPOSITORIES: Pride

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			Action	DRS
	20160815_MHAB-167-168_1.ms2	Other
	20160815_MHAB-167-168_1.mzXML	Mzxml
	20160815_MHAB-167-168_1.pride.mgf.gz	Mgf
	20160815_MHAB-167-168_2.ms2	Other
	20160815_MHAB-167-168_2.mzXML	Mzxml

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SILAC analysis of relative protein abundance in cytosol - AG3258 and AG11498

Project description:Premature aging disorders provide a lens through which to study the drivers of aging. In Hutchinson-Gilford progeria syndrome (HGPS) a mutant form of the nuclear scaffold protein lamin A distorts nuclei and sequesters nuclear proteins. We used stable isotope labeling and quantitative mass spectrometry to investigate nuclear protein abundance in primary HGPS-derived cells.

2017-07-07 | PXD006014 | Pride

SILAC analysis of relative protein abundance in nuclei - AG3258 and AG11498

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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. 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

NAT10 inhibition improves cellular phenotypes of Hutchinson-Gilford progeria syndrome by restoring the Transportin-1 pathway

Project description:In this experiment, we aim to examine the role of NAT10 inhibition in Hutchinson-Gilford progeria syndrome (HGPS), a rare but devastating premature ageing syndrome caused by a mutation in the LMNA gene. NAT10 inhibition improves HGPS cellular phenotypes by releasing Transportin-1 (TNPO1) from the cytoplasm, restoring the TNPO1 pathway and allowing hnRNPA1 and NUP153 nuclear import, TPR anchorage at the nuclear pore complexes and RanGTP gradient re-balancing. We have promoted NAT10 inhibition by two ways in normal or patient derived primary skin fibroblasts; the NAT10 inhibitor Remodelin, and an siRNA directly targeting NAT10 (siNAT10). In addition, we have also used an siRNA against TNPO1 and a combined siTNPO1 and siNAT10 treatment. This is a 2-factor design, with treatment (Remodelin vs untreated, or siNAT10 vs siCT) and condition (HGPS vs normal fibroblasts) as the two conditions. Transcriptional profiling was performed using HumanHT-12 v4 Expression BeadChip microarrays, and all conditions were run in triplicate.

2018-06-25 | E-MTAB-6651 | biostudies-arrayexpress

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

2011-03-14 | GSE24487 | GEO

PML2‐mediated thread‐like nuclear bodies mark late senescence in Hutchinson–Gilford progeria syndrome [ChIP-seq]

Project description:Regular nuclear structure is critical for genome maintenance and proper gene expression, disorder of which has a causal role in aging. Accumulation of Progerin in Hutchinson-Gilford progeria syndrome (HGPS) disrupts the integrity of nuclear lamina and causes nuclear structure abnormalities, leading to premature aging. However, the nuclear structure/function relationships in HGPS cells have not been well addressed, and roles of nuclear sub-compartments for HGPS pathogenesis are rarely reported. Here, evidence reveals that classical dot-like PML nuclear bodies (PML NBs) are reorganized into thread-like morphology in HGPS cells, and these irregular NBs are strongly associated with cell senescence. We demonstrate that farnesylated Progerin interacts with PML isoform 2 specifically, which accounts for the formation of thread-like PML NBs. Moreover, our findings uncover that irregular PML NBs perturb NBs-associated DNA repair and gene transcription, thereby promoting HGPS cell senescence. Thus, our work helps to clarify the roles of nuclear structure and sub-compartments such as PML NBs in cell aging, and evidence presented in this study strongly support that thread-like PML NBs could be a novel biomarker of human cell senescence.

2019-09-10 | GSE137084 | GEO

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