DNA methylation in PRDM8 is indicative for dyskeratosis congenita

Abstract

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.

PRDM8 exhibits antitumor activities toward hepatocellular carcinoma by targeting NAP1L1

“…However, no significant results were found (data not shown). In addition, previous works reported that reduced expression of PRDM8 was caused by hypermethylation in patients with dyskeratosis congenital, aplastic anemia, and Down syndrome . Based on our results, down‐regulated PRDM8 expression in HCC cell lines was not significantly restored by treatment with 5‐aza‐2′‐deoxycytidine (data not shown).…”

“…It is also possible that HES5 might be an upstream regulator of PRDM8. Aberrant hypermethylation of PRDM8 is observed in dyskeratosis congenital, aplastic anemia, Down syndrome, and Werner syndrome . PRDM8 has hypomethylated CpG islands in endometrial cancer .…”

Comparison of flow‐FISH and MM–qPCR telomere length assessment techniques for the screening of telomeropathies

“…Genetic variants/heterozygous mutations in telomere maintenance genes were screened using a self-designed panel containing the entire coding sequences for CTC1, DKC1, NHP2, NOP10, RTEL1, TERC, TERT, TCAB1, USB1, and exon 6 of TINF2. 20,21 Flow-FISH Vital sterile frozen MNC from PB was used for the flow-FISH analysis of TL, as previously described. [22][23][24][25][26] Briefly, samples were prepared for cell denaturation and mixed with an FITC-labeled telomere-specific (CCCTAA)3-peptide nucleic acid FISH probe (Eurogentec, Liège, Belgium) for DNA hybridization followed by DNA counterstaining with LDS 751 (Sigma).…”

Dyskeratosis congenita: ein Literaturüberblick

“…Des Weiteren ist eine Defizienz der Poly(A)‐spezifischen Ribonuklease, welche die Poly(A)‐Schwänze der mRNA kürzt und daher zum Silencing führt, mit Dyskeratosis congenita assoziiert, wobei Enzym‐depletierte Zellen einen niedrigen Gehalt spezifischer Ribonukleinsäuren aufweisen, die essenziell für die Aufrechterhaltung des Telomerase‐Komplexes sind . Die Telomerlänge scheint außerdem mit der Methylierung der Subtelomere assoziiert zu sein .…”