Open AccessReprogramming progeria fibroblasts re‐establishes a normal epigenetic landscape
Author(s) -
Chen Zhaoyi,
Chang Wing Y.,
Etheridge Alton,
Strickfaden Hilmar,
Jin Zhigang,
Palidwor Gareth,
Cho JiHoon,
Wang Kai,
Kwon Sarah Y.,
Doré Carole,
Raymond Angela,
Hotta Akitsu,
Ellis James,
Kandel Rita A.,
Dilworth F. Jeffrey,
Perkins Theodore J.,
Hendzel Michael J.,
Galas David J.,
Stanford William L.
Publication year - 2017
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12621
Subject(s) - biology , reprogramming , epigenetics , induced pluripotent stem cell , progeria , lamin , nuclear lamina , microbiology and biotechnology , lmna , genetics , cancer research , embryonic stem cell , cell , gene , nuclear protein , transcription factor
Summary Ideally, disease modeling using patient‐derived induced pluripotent stem cells ( iPSC s) 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 iPSC s, 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 iPSC s 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.