Journal
CLINICAL EPIGENETICS
Volume 12, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13148-020-00914-5
Keywords
PRDM8; Epigenetic clock; DNA methylation; Telomere; Aging; Dyskeratosis congenita; Aplastic anemia; iPSC; Hematopoietic differentiation; Neuronal differentiation
Categories
Funding
- German Research Foundation (DFG) [WA 1706/8-1, WA 1706/12-1, BR 1782/5-1, LA 2740/3-1, 363055819/GRK2415]
- Interdisciplinary Center for Clinical Research (IZKF) within the faculty of Medicine at the RWTH Aachen University [O3-3]
- Deutsche Krebshilfe
- Federal Ministry of Education and Research
- Flow Cytometry Facility, a core facility of the IZKF within the Faculty of Medicine at RWTH Aachen University
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Background: Dyskeratosis congenita (DKC) and idiopathic aplastic anemia (AA) are bone marrow failure syndromes that share characteristics of premature aging with severe telomere attrition. Aging is also reflected by DNA methylation changes, which can be utilized to predict donor age. There is evidence that such epigenetic age predictions are accelerated in premature aging syndromes, but it is yet unclear how this is related to telomere length. DNA methylation analysis may support diagnosis of DKC and AA, which still remains a challenge for these rare diseases. Results: In this study, we analyzed blood samples of 70 AA and 18 DKC patients to demonstrate that their epigenetic age predictions are overall increased, albeit not directly correlated with telomere length. Aberrant DNA methylation was observed in the genePRDM8in DKC and AA as well as in other diseases with premature aging phenotype, such as Down syndrome and Hutchinson-Gilford-Progeria syndrome. Aberrant DNA methylation patterns were particularly found within subsets of cell populations in DKC and AA samples as measured with barcoded bisulfite amplicon sequencing (BBA-seq). To gain insight into the functional relevance of PRDM8, we used CRISPR/Cas9 technology to generate induced pluripotent stem cells (iPSCs) with heterozygous and homozygous knockout. Loss of PRDM8 impaired hematopoietic and neuronal differentiation of iPSCs, even in the heterozygous knockout clone, but it did not impact on epigenetic age. Conclusion: Taken together, our results demonstrate that epigenetic aging is accelerated in DKC and AA, independent from telomere attrition. Furthermore, aberrant DNA methylation inPRDM8provides another biomarker for bone marrow failure syndromes and modulation of this gene in cellular subsets may be related to the hematopoietic and neuronal phenotypes observed in premature aging syndromes.
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