Weidner Carola I, Lin Qiong, Birkhofer Carina, Gerstenmaier Uwe, Kaifie Andrea, Kirschner Martin, Bruns Heiko, Balabanov Stefan, Trummer Arne, Stockklausner Clemens, Höchsmann Britta, Schrezenmeier Hubert, Wlodarski Marcin, Panse Jens, Brümmendorf Tim H, Beier Fabian, Wagner Wolfgang
Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University Medical Faculty, Aachen, Germany.
Institute for Biomedical Technology - Cell Biology, RWTH University Medical School, Aachen, Germany.
Oncotarget. 2016 Mar 8;7(10):10765-72. doi: 10.18632/oncotarget.7458.
Dyskeratosis congenita (DKC) is associated with impaired telomere maintenance and with clinical features of premature aging. In this study, we analysed global DNA methylation (DNAm) profiles of DKC patients. Age-associated DNAm changes were not generally accelerated in DKC, but there were significant differences to DNAm patterns of healthy controls, particularly in CpG sites related to an internal promoter region of PR domain containing 8 (PRDM8). Notably, the same genomic region was also hypermethylated in aplastic anemia (AA) - another bone marrow failure syndrome. Site-specific analysis of DNAm level in PRDM8 with pyrosequencing and MassARRAY validated aberrant hypermethylation in 11 DKC patients and 27 AA patients. Telomere length, measured by flow-FISH, did not directly correlate with DNAm in PRDM8. Therefore the two methods may be complementary to also identify patients with still normal telomere length. In conclusion, blood of DKC patients reveals aberrant DNAm patterns, albeit age-associated DNAm patterns are not generally accelerated. Aberrant hypermethylation is particularly observed in PRDM8 and this may support identification and classification of bone marrow failure syndromes.
先天性角化不良（DKC）与端粒维持受损以及早衰的临床特征相关。在本研究中，我们分析了DKC患者的全基因组DNA甲基化（DNAm）图谱。在DKC中，与年龄相关的DNAm变化通常并未加速，但与健康对照的DNAm模式存在显著差异，尤其是在与含PR结构域8（PRDM8）内部启动子区域相关的CpG位点。值得注意的是，在再生障碍性贫血（AA）——另一种骨髓衰竭综合征中，同一基因组区域也发生了高甲基化。通过焦磷酸测序和MassARRAY对PRDM8中的DNAm水平进行位点特异性分析，证实了11例DKC患者和27例AA患者存在异常高甲基化。通过流式荧光原位杂交（flow-FISH）测量的端粒长度与PRDM8中的DNAm无直接相关性。因此，这两种方法可能具有互补性，也可用于识别端粒长度仍正常的患者。总之，DKC患者的血液显示出异常的DNAm模式，但与年龄相关的DNAm模式通常并未加速。在PRDM8中尤其观察到异常高甲基化，这可能有助于骨髓衰竭综合征的识别和分类。
