title: The relationship between DNA methylation and telomere length in dyskeratosis congenita.
abstract: The regulation of telomere length (TL) is a complex process, requiring the telomerase enzyme complex and numerous regulatory proteins. Epigenetic regulation may also be important in telomere maintenance. Specifically, methylation at subtelomeres is associated with changes in TL in vitro and in mouse models. Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by exceedingly short telomeres and mutations in telomere biology genes. To understand the interaction between methylation and TL in humans, we measured LINE-1, pericentromeric (NBL2), and subtelomeric (D4Z4) methylation in peripheral blood DNA derived from 40 patients with DC and 51 mutation-negative relatives. Pearson's correlation coefficient and linear regression models were used to evaluate the relationship between age-standardized lymphocyte TL measured by flow FISH and % DNA methylation. No differences in % subtelomeric, LINE-1, or pericentromeric methylation between patients with DC and relatives were noted except for an increase in % subtelomeric methylation in DC patients with a telomerase-complex mutation (TERC, TERT, DKC1, or TCAB1) (63.0% in DC vs. 61.8% in relatives, P = 0.03). Positive correlations between TL and DNA methylation at LINE-1 (r = 0.39, P = 0.01) and subtelomeric (r = 0.32, P = 0.05) sites were present in patients with DC. The positive correlation between TL and % LINE-1 methylation was restricted to TINF2 mutations. In contrast, statistically nonsignificant inverse correlations between TL and % LINE-1 (r = -0.17), subtelomeric (r = -0.20) were present in unaffected relatives. This study suggests an interaction between TL and both subtelomeric and LINE-1 methylation, which may be altered based on mutation status of telomere biology genes.
authors: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD 20852, USA.
authors: Shahinaz M
authors: SM
authors: Gadalla
authors: Hormuzd A
authors: HA
authors: Katki
authors: Fatma M
authors: FM
authors: Shebl
authors: Neelam
authors: N
authors: Giri
authors: Blanche P
authors: BP
authors: Alter
authors: Sharon A
authors: SA
authors: Savage
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D019871:Dyskeratosis Congenita / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D018832:Molecular Chaperones; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D012313:RNA / Q000235:genetics; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000235:genetics*; D059505:Telomere Homeostasis; D034501:Telomere-Binding Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C440868:TINF2 protein, human; D034501:Telomere-Binding Proteins; C422952:telomerase RNA; D012313:RNA; C509186:TERT protein, human; D019098:Telomerase; C535133:WRAP53 protein, human