Epigenetic deregulation of lamina-associated domains in Hutchinson-Gilford progeria syndrome

Abstract

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.

Epigenomic signature of the progeroid Cockayne syndrome exposes distinct and common features with physiological ageing

“…Collectively, data from previous studies 25,27,28,39 and our new analyses demonstrate that epigenetic remodelling is a common hallmark of progeroid syndromes. At the same time, as pointed out in the seminal study of George Martin 62 , commonalities and differences exist for changes occurring in progeroid disorders versus physiological aging.…”

“…These results differ from those recently reported in WS whole blood cells, were only 6% of DMPs displayed age-associated DNA methylation changes 39 . Similarly, it was recently reported that epigenetic changes in HGPS fibroblasts differ from those occurring during physiological aging 28 . Our data thus suggest that CS DNA methylation changes are closer to normal ageing than other progeroid diseases, and confirm CS as a precocious ageing disorder.…”

Mutations Involved in Premature-Ageing Syndromes

“…6 Particularly, HGPS cells accumulate structural and mechanical defects of the nuclear lamina with passaging, resulting from the accumulation of progerin and leading to bigger and dysmorphic nuclei with thickening of the nuclear lamina, lobulations, clustering of nuclear pores, and disorganization of chromatin, coupled to changes in DNA methylation and histone tail modifications leading to a widespread transcriptional misregulation. 6,[9][10][11] Fibroblasts from HGPS patients also exhibit accumulation of DNA damage, defective DNA repair and chromosomal instability with cell passaging, as well as mitochondrial dysfunction and a faster telomere shortening. 12 Several other LMNA mutations causing a progeroid phenotype have so far been described, and are collected in the updated LMNA mutations database (UMD-LMNA: http://www.umd.…”

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

“…As it has recently been appreciated that Lamin A and the nuclear lamina play an important role in mediating transfer of information from the cytoplasm to the nucleus, the altered nuclear structure due the presence of progerin in HGPS may hinder or promote transfer of this information across the nuclear boundary, leading to deregulated gene expression (Kelley et al, 2011;Wilson, 2018). In addition, progerin may have a more direct effect on miR-145 expression, as recent studies have shown that HGPS nuclei have a dramatically altered epigenetic signature which can lead to improper gene silencing or activation (Arancio et al, 2014;Köhler et al, 2020). Altered LOX and miR-145 expression in HGPS could also be a secondary effect of long-term progerin expression, perhaps with progerin-expressing SMCs secreting altered chemokines to promote vascular remodeling in HGPS.…”