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. 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. 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.

中文翻译：

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PRDM8 揭示了衰老综合征中的异常 DNA 甲基化，并且与造血和神经元分化相关。


先天性角化不良 (DKC) 和特发性再生障碍性贫血 (AA) 是骨髓衰竭综合征，具有过早衰老和严重端粒磨损的共同特征。 DNA 甲基化的变化也反映了衰老，可以用来预测捐献者的年龄。有证据表明，这种表观遗传年龄预测在早衰综合症中会加速，但尚不清楚这与端粒长度有何关系。 DNA 甲基化分析可能支持 DKC 和 AA 的诊断，这对于这些罕见疾病仍然是一个挑战。在这项研究中，我们分析了 70 名 AA 和 18 名 DKC 患者的血液样本，以证明他们的表观遗传年龄预测总体上有所增加，尽管与端粒长度没有直接相关。在 DKC 和 AA 以及其他具有早衰表型的疾病（例如唐氏综合症和哈钦森-吉尔福德-早衰综合症）中，在基因 PRDM8 中观察到异常 DNA 甲基化。通过条形码亚硫酸氢盐扩增子测序 (BBA-seq) 测量，异常 DNA 甲基化模式尤其在 DKC 和 AA 样品的细胞群亚群中发现。为了深入了解 PRDM8 的功能相关性，我们使用 CRISPR/Cas9 技术生成具有杂合和纯合敲除的诱导多能干细胞 (iPSC)。 PRDM8的缺失会损害iPSC的造血和神经元分化，即使在杂合敲除克隆中也是如此，但它并不影响表观遗传年龄。综上所述，我们的结果表明，DKC 和 AA 中表观遗传衰老加速，与端粒磨损无关。 此外，PRDM8 中的异常 DNA 甲基化提供了骨髓衰竭综合征的另一种生物标志物，细胞亚群中该基因的调节可能与早衰综合征中观察到的造血和神经元表型有关。