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Project description:BackgroundHutchinson-Gilford progeria syndrome (HGPS) is a progeroid disease characterized by the early onset of 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 histone modification changes.MethodsHere, we analyze the possibility that epigenetic deregulation of lamina-associated domains (LADs) is involved in the molecular pathology of HGPS. To do so, we studied chromatin accessibility (Assay for Transposase-accessible Chromatin (ATAC)-see/-seq), DNA methylation profiles (Infinium MethylationEPIC BeadChips), and transcriptomes (RNA-seq) of nine primary HGPS fibroblast cell lines and six additional controls, two parental and four age-matched healthy fibroblast cell lines.ResultsOur ATAC-see/-seq data demonstrate that primary dermal fibroblasts from HGPS patients exhibit chromatin accessibility changes that are enriched in LADs. Infinium MethylationEPIC BeadChip profiling further reveals that DNA methylation alterations observed in HGPS fibroblasts are similarly enriched in LADs and different from those occurring during healthy aging and Werner syndrome (WS), another premature aging disease. Moreover, HGPS patients can be stratified into two different subgroups according to their DNA methylation profiles. Finally, we show that the epigenetic deregulation of LADs is associated with HGPS-specific gene expression changes.ConclusionsTaken together, our results strongly implicate epigenetic deregulation of LADs as an important and previously unrecognized feature of HGPS, which contributes to disease-specific gene expression. Therefore, they not only add a new layer to the study of epigenetic changes in the progeroid syndrome, but also advance our understanding of the disease's pathology at the cellular level.
| S-EPMC7249329 | biostudies-literature
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
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.
2020-05-08 | GSE150136 | GEO
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.
2020-05-08 | GSE150137 | GEO
Project description:Epigenetic deregulation of lamina-associated domains in Hutchinson-Gilford Progeria Syndrome
| PRJNA630703 | ENA
Project description:Epigenetic deregulation of lamina-associated domains in Hutchinson-Gilford Progeria Syndrome
| PRJNA631244 | ENA
Project description:Epigenetic deregulation of lamina-associated domains in Hutchinson-Gilford Progeria Syndrome (RNA-Seq)
| PRJNA631248 | ENA
Project description:Epigenetic deregulation of lamina-associated domains in Hutchinson-Gilford Progeria Syndrome (ATAC-Seq)
| PRJNA631249 | ENA
Project description:The nuclear lamina is a network of structural filaments, the A and B type lamins, located at the nuclear envelope and throughout the nucleus. Lamin filaments provide the nucleus with mechanical stability and support many basic activities, including gene regulation. Mutations in LMNA, the gene encoding A type lamins, cause numerous human diseases, including the segmental premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). Here we show that structural and mechanical properties of the lamina are altered in HGPS cells. We demonstrate by live-cell imaging and biochemical analysis that lamins A and C become trapped at the nuclear periphery in HGPS patient cells. Using micropipette aspiration, we show that the lamina in HGPS cells has a significantly reduced ability to rearrange under mechanical stress. Based on polarization microscopy results, we suggest that the lamins are disordered in the healthy nuclei, whereas the lamins in HGPS nuclei form orientationally ordered microdomains. The reduced deformability of the HGPS nuclear lamina possibly could be due to the inability of these orientationally ordered microdomains to dissipate mechanical stress. Surprisingly, intact HGPS cells exhibited a degree of resistance to acute mechanical stress similar to that of cells from healthy individuals. Thus, in contrast to the nuclear fragility seen in lmna null cells, the lamina network in HGPS cells has unique mechanical properties that might contribute to disease phenotypes by affecting responses to mechanical force and misregulation of mechanosensitive gene expression.
| S-EPMC1502447 | biostudies-literature
Project description:Hutchinson-Gilford progeria syndrome is a premature aging disorder associated with the expression of ?50 lamin A (?50LA), a mutant form of the nuclear structural protein lamin A (LA). ?50LA is missing 50 amino acids from the tail domain and retains a C-terminal farnesyl group that is cleaved from the wild-type LA. Many of the cellular pathologies of HGPS are thought to be a consequence of protein-membrane association mediated by the retained farnesyl group. To better characterize the protein-membrane interface, we quantified binding of purified recombinant ?50LA tail domain (?50LA-TD) to tethered bilayer membranes composed of phosphatidylserine and phosphocholine using surface plasmon resonance. Farnesylated ?50LA-TD binds to the membrane interface only in the presence of Ca(2+) or Mg(2+) at physiological ionic strength. At extremely low ionic strength, both the farnesylated and non-farnesylated forms of ?50LA-TD bind to the membrane surface in amounts that exceed those expected for a densely packed protein monolayer. Interestingly, the wild-type LA-TD with no farnesylation also associates with membranes at low ionic strength but forms only a single layer. We suggest that electrostatic interactions are mediated by charge clusters with a net positive charge that we calculate on the surface of the LA-TDs. These studies suggest that the accumulation of ?50LA at the inner nuclear membrane observed in cells is due to a combination of aggregation and membrane association rather than simple membrane binding; electrostatics plays an important role in mediating this association.
| S-EPMC4212650 | biostudies-literature