Telomere length changes during genome-wide epigenetic reprogramming in human preimplantation embryos

We report on the telomere length (TL) changes in metaphase chromosomes throughout preimplantation development of human embryos-a period of genome-wide epigenetic reprogramming. Using semiquantitative fluorescence in situ hybridization, we measured relative TLs in the metaphase chromosomes of 69 preimplantation embryos from the zygote up to and including the blastocyst stage. Relative TLs increased significantly from zygote to the 2-5-cell stage, remained almost unchanged at the stages of 2-5 and 6-12-cells and decreased by the blastocyst stage. Concurrently with relative TL decrease at the blastocyst stage, an increase in interindividual TL variability occurred. The zygote-inherited, but not newly synthesized chromatids maintained parent-specific telomeres (longer in paternal compared to maternal chromosomes) up to and including the 2-5-cell stage, with a follow-up TL equalization in 6-12-cell embryos. The extent of interchromatid TL asymmetry-a phenomenon potentially linked to telomere lengthening through recombination-was assessed by TL ratios between sister chromatids and showed similar patterns across all stages of preimplantation development. The longer telomere is presumably located in the highly hydroxymethylated sister chromatid of hemihydroxymethylated chromosomes, i.e., those having higher 5-hydroxymethylcytosine content in one sister chromatid than in the other due to global epigenetic reprogramming in early embryogenesis. To conclude, our study suggests that in human preimplantation development telomeres are reprogrammed in conjunction with genome-wide epigenetic reprogramming of an embryo. By the blastocyst stage, when epigenetic reprogramming comes to an end, parent-specific TLs are also completely reprogrammed and every embryo develops its own unique TL pattern.