Hypomethylation of subtelomeric regions in ICF syndrome is associated with abnormally short telomeres and enhanced transcription from telomeric regions

被引:179
作者
Yehezkel, Shiran [1 ,2 ,3 ,4 ]
Segev, Yardena [1 ,2 ,3 ,4 ]
Viegas-Pequignot, Evani [5 ]
Skorecki, Karl [1 ,2 ,3 ,4 ]
Selig, Sara [1 ,2 ,3 ,4 ]
机构
[1] Technion Israel Inst Technol, Rambam Med Ctr, Dept Nephrol, IL-31096 Haifa, Israel
[2] Technion Israel Inst Technol, Rambam Med Ctr, Mol Med Lab, IL-31096 Haifa, Israel
[3] Technion Israel Inst Technol, Rappaport Fac Med, IL-31096 Haifa, Israel
[4] Technion Israel Inst Technol, Res Inst, IL-31096 Haifa, Israel
[5] Univ Paris 07, INSERM, U741, F-75251 Paris, France
基金
以色列科学基金会;
关键词
D O I
10.1093/hmg/ddn177
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Telomeres and adjacent subtelomeric regions are packaged as heterochromatin in many organisms. The heterochromatic features include DNA methylation, histones H3-Lys9 (Lysine 9) and H4-Lys20 (Lysine 20) methylation and heterochromatin protein1 alpha binding. Subtelomeric DNA is hypomethylated in human sperm and ova, and these regions are subjected to de novo methylation during development. In mice this activity is carried out by DNA methyltransferase 3b (Dnmt3b). Mutations in DNMT3B in humans lead to the autosomal-recessive ICF (immunodeficiency, centromeric region instability, facial anomalies) syndrome. Here we show that, in addition to several satellite and non-satellite repeats, the subtelomeric regions in lymphoblastoid and fibroblast cells of ICF patients are also hypomethylated to similar levels as in sperm. Furthermore, the telomeres are abnormally short in both the telomerase-positive and -negative cells, and many chromosome ends lack detectable telomere fluorescence in situ hybridization signals from either one or both sister-chromatids. In contrast to Dnmt3a/b(-/-) mouse embryonic stem cells, increased telomere sister-chromatid exchange was not observed in ICF cells. Hypomethylation of subtelomeric regions was associated in the ICF cells with advanced telomere replication timing and elevated levels of transcripts emanating from telomeric regions, known as TERRA (telomeric-repeat-containing RNA) or TelRNA. The current findings provide a mechanistic explanation for the abnormal telomeric phenotype observed in ICF syndrome and highlights the link between TERRA/TelRNA and structural telomeric integrity.
引用
收藏
页码:2776 / 2789
页数:14
相关论文
共 98 条
[1]   RNAPol-ChIP analysis of transcription from FSHD-linked tandem repeats and satellite DNA [J].
Alexiadis, Vassilios ;
Ballestas, Mary E. ;
Sanchez, Cecilia ;
Winokur, Sara ;
Vedanarayanan, Vettaikorumakankav ;
Warren, Mary ;
Ehrlich, Melanie .
BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION, 2007, 1769 (01) :29-40
[2]   Telomeric repeat-containing RNA and RNA surveillance factors at mammalian chromosome ends [J].
Azzalin, Claus M. ;
Reichenbach, Patrick ;
Khoriauli, Lela ;
Giulotto, Elena ;
Lingner, Joachim .
SCIENCE, 2007, 318 (5851) :798-801
[3]   Dnmt3a and Dnmt3b are transcriptional repressors that exhibit unique localization properties to heterochromatin [J].
Bachman, KE ;
Rountree, MR ;
Baylin, SB .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (34) :32282-32287
[4]   Strand-specific fluorescence in situ hybridization: the CO-FISH family [J].
Bailey, SM ;
Goodwin, EH ;
Cornforth, MN .
CYTOGENETIC AND GENOME RESEARCH, 2004, 107 (1-2) :14-17
[5]   Frequent recombination in telomeric DNA may extend the proliferative life of telomerase-negative cells [J].
Bailey, SM ;
Brenneman, MA ;
Goodwin, EH .
NUCLEIC ACIDS RESEARCH, 2004, 32 (12) :3743-3751
[6]   Telomeres, chromosome instability and cancer [J].
Bailey, Susan M. ;
Murnane, John P. .
NUCLEIC ACIDS RESEARCH, 2006, 34 (08) :2408-2417
[7]   Telomere length regulates the epigenetic status of mammalian telomeres and subtelomeres [J].
Benetti, Roberta ;
Garcia-Cao, Marta ;
Blasco, Maria A. .
NATURE GENETICS, 2007, 39 (02) :243-250
[8]   Sex brings transposons and genomes into conflict [J].
Bestor, TH .
GENETICA, 1999, 107 (1-3) :289-295
[9]   The DNA methyltransferases of mammals [J].
Bestor, TH .
HUMAN MOLECULAR GENETICS, 2000, 9 (16) :2395-2402
[10]   Early replication of short telomeres in budding yeast [J].
Bianchi, Alessandro ;
Shore, David .
CELL, 2007, 128 (06) :1051-1062