PRDM8 reveals aberrant DNA methylation in aging syndromes and is relevant for hematopoietic and neuronal differentiation

Clinical Epigenetics

Margherita Vieri¹  Tim H. Brümmendorf¹  Martin Kirschner¹  Fabian Beier¹  Vithurithra Tharmapalan²  Chao-Chung Kuo²  Olivia Cypris²  Monika Eipel²  Julia Franzen²  Miloš Nikolić²  Martin Zenke³  Wolfgang Wagner³  Angelika Lampert⁴  Corinna Rösseler⁴ 

[1] Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty University Hospital Aachen, RWTH Aachen University, Aachen, Germany;Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH Aachen University, Pauwelsstrasse 20, Aachen, Germany;Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH Aachen University, Pauwelsstrasse 20, Aachen, Germany;Institute for Biomedical Engineering – Cell Biology, RWTH Aachen University Medical School, Aachen, Germany;Institute of Physiology, Medical Faculty University Hospital Aachen, RWTH Aachen University, Aachen, Germany;

关键词: PRDM8;    Epigenetic clock;    DNA methylation;    Telomere;    Aging;    Dyskeratosis congenita;    Aplastic anemia;    iPSC;    Hematopoietic differentiation;    Neuronal differentiation;   

DOI  :  10.1186/s13148-020-00914-5

来源: Springer

【 摘 要 】

BackgroundDyskeratosis 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.ResultsIn 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.ConclusionTaken 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.Graphical abstract

【 授权许可】

CC BY