BACKGROUND: Hutchinson-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.
METHODS: Here, 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.
RESULTS: Our 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.
CONCLUSIONS: Taken 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.