Abstract
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
Highlights
Dyskeratosis congenita (DKC) and idiopathic aplastic anemia (AA) are bone marrow failure syndromes that share characteristics of premature aging with severe telomere attrition
Telomere attrition and accelerated epigenetic aging in bone marrow failure syndromes Telomere length was measured in granulocytes of 65 AA and 17 DKC patients
We analyzed epigenetic age in these samples using our previously described epigenetic aging signature based on DNA methylation at three CpGs within the genes phosphodiesterase 4C (PDE4C; CpG next to cg17861230, which is not presented by the Illumina BeadChip), integrin alpha 2b (ITGA2B; cg25809905), and aspartoacylase (ASPA; cg02228185) [17]
Summary
Dyskeratosis congenita (DKC) and idiopathic aplastic anemia (AA) are bone marrow failure syndromes that share characteristics of premature aging with severe telomere attrition. DNA methylation analysis may support diagnosis of DKC and AA, which still remains a challenge for these rare diseases Premature aging syndromes, such as Down syndrome, Werner syndrome, or dyskeratosis congenita (DKC), are often associated with impaired neurologic development or hematological abnormalities [1,2,3]. In acquired AA, telomere length in the granulocyte compartment can show substantial attrition and was shown to reflect the degree of autoimmune-mediated damage to the hematopoietic stem cell compartment [11]. This may hamper correct diagnosis of DKC [12], which is of utmost importance since DKC, in contrast to acquired AA, is not responding to immunosuppressive therapy and requires optimized conditioning protocols in case of allogeneic stem cell transplantation [13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
