Epigenetic regulation of telomere chromatin integrity in pluripotent embryonic stem cells

Telomeres are protective chromosomal structures highly conserved from primitive organisms to humans. The evolutionary conservation of telomere DNA implicates the importance of telomeric structure for basic cellular functions. Loss of telomere function causes chromosomal fusion, activation of DNA damage checkpoint responses, genome instability and impaired stem cell function. In human cells, the telomeric chromatin consists of TTAGGG repeats associated with a complex of proteins known as Shelterin. It is also organized in nucleosomes enriched with epigenetic modifications of 'closed' or 'silenced' chromatin states, including DNA hypermethylation and trimethylation of H3K9 and H4K20. These heterochromatin marks serve as a higher-order level of control of telomere length and structural integrity. Recent studies have shown that the telomere nucleosome in pluripotent embryonic stem cells is characterized by a more 'open' chromatin state that switches to become more repressive during differentiation. Conversely, the reprogramming of adult somatic cells into induced pluripotent cells results in the switch in telomeric chromatin from a repressive to a more open embryonic stem cell-like state, coupled with the restoration of telomere length. These findings indicate that telomeric chromatin is dynamic and reprogrammable, and has a fundamental role in the maintenance of embryonic stem cell pluripotency.