PRDM8 reveals aberrant DNA methylation in aging syndromes and is relevant for hematopoietic and neuronal differentiation
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RESEARCH
Open Access
PRDM8 reveals aberrant DNA methylation in aging syndromes and is relevant for hematopoietic and neuronal differentiation Olivia Cypris1†, Monika Eipel1†, Julia Franzen1, Corinna Rösseler2, Vithurithra Tharmapalan1, Chao-Chung Kuo1, Margherita Vieri3, Miloš Nikolić1, Martin Kirschner3, Tim H. Brümmendorf3, Martin Zenke1,4, Angelika Lampert2, Fabian Beier3† and Wolfgang Wagner1,4*†
Abstract 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 gene PRDM8 in 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 in PRDM8 provides 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. Keywords: PRDM8, Epigenetic clock, DNA methylation, Telomere, Aging, Dyskeratosis congenita, Aplastic anemia, iPSC, Hematopoietic differentiation, Neuronal differentiation * Correspondence: [email protected] † Olivia Cypris, Monika Eipel, Fabian Beier and Wolfgang Wagner contributed equally to this work. 1 Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH Aachen University, Pauwelsstrasse 20, Aachen, Germany 4 Institute for Biomedical Engineering – Cell Biology, RWTH Aachen University Medical School, Aachen, Germany Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, wh
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