TY - JOUR
T1 - Induced pluripotent stem cells as a model for telomeric abnormalities in ICF type I syndrome
AU - Sagie, Shira
AU - Ellran, Erika
AU - Katzir, Hagar
AU - Shaked, Rony
AU - Yehezkel, Shiran
AU - Laevsky, Ilana
AU - Ghanayim, Alaa
AU - Geiger, Dan
AU - Tzukerman, Maty
AU - Selig, Sara
N1 - Funding Information: This research was supported by THE ISRAEL SCIENCE FOUNDATION (grant No. 883/12 to Sara Selig).
PY - 2014/7
Y1 - 2014/7
N2 - Human telomeric regions are packaged as constitutive heterochromatin, characterized by extensive subtelomeric DNA methylation and specific histone modifications. ICF (immunodeficiency, centromeric instability, facial anomalies) type I patients carry mutations in DNA methyltransferase 3B (DNMT3B) that methylates de novo repetitive sequences during early embryonic development. ICF type I patient fibroblasts display hypomethylated subtelomeres, abnormally short telomeres and premature senescence. In order to study the molecular mechanism by which the failure to de novo methylate subtelomeres results in accelerated telomere shortening,wegenerated induced pluripotent stem cells (iPSCs) from 3 ICF type I patients.Telomeres were elongated in ICF-iPSCs during reprogramming, and the senescence phenotype was abolished despite sustained subtelomeric hypomethylation and high TERRA levels. Fibroblast-like cells (FLs) isolated from differentiated ICF-iPSCs maintained abnormally high TERRA levels, and telomeres in these cells shortened at an accelerated rate, leading to early senescence, thus recapitulating the telomeric phenotype of the parental fibroblasts. These findings demonstrate that the abnormal telomere phenotype associated with subtelomeric hypomethylation is overridden in cells expressing telomerase, therefore excluding telomerase inhibition by TERRA as a central mechanism responsible for telomere shortening in ICF syndrome. The data in the current study lend support to the use of ICF-iPSCs for modeling of phenotypic and molecular defects in ICF syndrome and for unraveling themechanism whereby subtelomerichypomethylation is linked to accelerated telomeric loss in this syndrome.
AB - Human telomeric regions are packaged as constitutive heterochromatin, characterized by extensive subtelomeric DNA methylation and specific histone modifications. ICF (immunodeficiency, centromeric instability, facial anomalies) type I patients carry mutations in DNA methyltransferase 3B (DNMT3B) that methylates de novo repetitive sequences during early embryonic development. ICF type I patient fibroblasts display hypomethylated subtelomeres, abnormally short telomeres and premature senescence. In order to study the molecular mechanism by which the failure to de novo methylate subtelomeres results in accelerated telomere shortening,wegenerated induced pluripotent stem cells (iPSCs) from 3 ICF type I patients.Telomeres were elongated in ICF-iPSCs during reprogramming, and the senescence phenotype was abolished despite sustained subtelomeric hypomethylation and high TERRA levels. Fibroblast-like cells (FLs) isolated from differentiated ICF-iPSCs maintained abnormally high TERRA levels, and telomeres in these cells shortened at an accelerated rate, leading to early senescence, thus recapitulating the telomeric phenotype of the parental fibroblasts. These findings demonstrate that the abnormal telomere phenotype associated with subtelomeric hypomethylation is overridden in cells expressing telomerase, therefore excluding telomerase inhibition by TERRA as a central mechanism responsible for telomere shortening in ICF syndrome. The data in the current study lend support to the use of ICF-iPSCs for modeling of phenotypic and molecular defects in ICF syndrome and for unraveling themechanism whereby subtelomerichypomethylation is linked to accelerated telomeric loss in this syndrome.
UR - http://www.scopus.com/inward/record.url?scp=84902950615&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/hmg/ddu071
DO - https://doi.org/10.1093/hmg/ddu071
M3 - مقالة
SN - 0964-6906
VL - 23
SP - 3629
EP - 3640
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 14
M1 - ddu071
ER -