Abstract
SummaryIdeally, disease modeling using patient‐derived induced pluripotent stem cells (iPSCs) enables analysis of disease initiation and progression. This requires any pathological features of the patient cells used for reprogramming to be eliminated during iPSC generation. Hutchinson–Gilford progeria syndrome (HGPS) is a segmental premature aging disorder caused by the accumulation of the truncated form of Lamin A known as Progerin within the nuclear lamina. Cellular hallmarks of HGPS include nuclear blebbing, loss of peripheral heterochromatin, defective epigenetic inheritance, altered gene expression, and senescence. To model HGPS using iPSCs, detailed genome‐wide and structural analysis of the epigenetic landscape is required to assess the initiation and progression of the disease. We generated a library of iPSC lines from fibroblasts of patients with HGPS and controls, including one family trio. HGPS patient‐derived iPSCs are nearly indistinguishable from controls in terms of pluripotency, nuclear membrane integrity, as well as transcriptional and epigenetic profiles, and can differentiate into affected cell lineages recapitulating disease progression, despite the nuclear aberrations, altered gene expression, and epigenetic landscape inherent to the donor fibroblasts. These analyses demonstrate the power of iPSC reprogramming to reset the epigenetic landscape to a revitalized pluripotent state in the face of widespread epigenetic defects, validating their use to model the initiation and progression of disease in affected cell lineages.
Highlights
Hutchinson–Gilford progeria syndrome (HGPS) is a rare and debilitating disease that affects one in four million live births (Merideth et al, 2008)
To assess the disease state in our patient samples used for reprogramming and the capacity of reprogramming to re-establish a normal pluripotent epigenetic landscape in induced pluripotent stem cells (iPSCs), we first focused on characterizing these hallmark defects in our HGPS patient fibroblasts
The iPSCs originating from the trio of the parents (168 090) and the affected child (167) did not segregate in the clustering analysis nor by principle component analysis (PCA) (Fig. S2), showing that there were no differences between the related and unrelated controls and patients with HGPS in undifferentiated cells at the gene expression level. These results suggest that despite the presence of defects associated with Progerin in the nuclear lamina including structural defects, senescence, and abnormal epigenetic marks, HGPS fibroblasts can be reprogrammed into iPSCs with transcriptomes that are highly similar to control iPSCs and hESCs
Summary
Hutchinson–Gilford progeria syndrome (HGPS) is a rare and debilitating disease that affects one in four million live births (Merideth et al, 2008). This segmental aging syndrome is usually diagnosed within the first 2 years of life, and is characterized by a rapid progression of agingrelated tissue pathologies, including osteoporosis, scleroderma, lipodystrophy, alopecia, hearing loss, and arteriosclerosis (Capell & Collins, 2006; Merideth et al, 2008). It has been hypothesized that Progerin accumulation contributes to the pathology of aging, leading to the use of the HGPS as a general model for aging
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