Progeroid syndromes are rare genetic disorders that phenotypically resemble natural aging. Different causal mutations have been identified, but no molecular alterations have been identified that are in common to these diseases. DNA replication timing (RT) is a robust cell type-specific epigenetic feature highly conserved in the same cell types from different individuals but altered in disease. Here, we characterized DNA RT program alterations in Hutchinson-Gilford progeria syndrome (HGPS) and Rothmund-Thomson syndrome (RTS) patients compared with natural aging and cellular senescence. Our results identified a progeroid-specific RT signature that is common to cells from three HGPS and three RTS patients and distinguishes them from healthy individuals across a wide range of ages. Among the RT abnormalities, we identified the tumor protein p63 gene (TP63) as a gene marker for progeroid syndromes. By using the redifferentiation of four patient-derived induced pluripotent stem cells as a model for the onset of proge-roid syndromes, we tracked the progression of RT abnormalities during development, revealing altered RT of the TP63 gene as an early event in disease progression of both HGPS and RTS. Moreover, the RT abnormalities in progeroid patients were associated with altered isoform expression of TP63. Our findings demonstrate the value of RT studies to identify biomarkers not detected by other methods, reveal abnormal TP63 RT as an early event in progeroid disease progression, and suggest TP63 gene regulation as a potential therapeutic target.
|Original language||English (US)|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Dec 19 2017|
Bibliographical noteFunding Information:
ACKNOWLEDGMENTS. We thank Ruth A. Didier for assistance with flow cytometry, Jared Zimmerman for data deposition in public repositories, Nard Kubben and Tom Misteli for sharing the progerin-GFP and lamin A-GFP cell lines, Armando Aranda-Anzaldo for critical reading of the manuscript, and la Région Languedoc Roussillon/Occitanie for a Ph.D. Student Fellowship. This work was supported by NIH Grants GM083337 and GM085354 (to D.M.G.), la Ligue Nationale Contre le Cancer Grant “Programme Labellisation Equipe 2015” (EL2015.LNCC/JML to J.-M.L.), INGESTEM National Infrastructure in Biology and Health, and le Centres Hospitaliers Universitaires de Montpellier.
- DNA replication timing
- Progeroid diseases
- RT signatures
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't