POT-1 telomere binding protein promotes a novel form of Transgenerational Epigenetic Inheritance

Transgenerational Epigenetic Inheritance occurs when gametes transmit forms of information without altering genomic DNA1. Although deficiency for telomerase in human families causes transgenerational shortening of telomeres2, a role for telomeres in Transgenerational Epigenetic Inheritance is unknown. Here we show that Protection Of Telomeres 1 (Pot1) proteins, which interact with single-stranded telomeric DNA3,4, function in gametes to regulate developmental expression of telomeric foci for multiple generations. C. elegans POT-1 and POT-25,6 formed abundant telomeric foci in adult germ cells that vanished in 1-cell embryos and gradually accumulated during development. pot-2 mutants displayed abundant POT-1::mCherry foci throughout development. pot-2 mutant gametes created F1 cross-progeny with constitutively abundant POT-1::mCherry and mNeonGreen::POT-2 foci, which persisted for 6 generations but did not alter telomere length. pot-1 mutant and pot-2; pot-1 double mutant gametes gave rise to progeny with constitutively diminished Pot1 foci. Genomic silencing and small RNAs potentiate many transgenerational effects7 but did not affect Pot1 foci. We conclude that C. elegans POT-1 functions at telomeres of pot-2 mutant gametes to create constitutively high levels of Pot1 foci in future generations. As regulation of telomeres and Pot1 have been tied to cancer8,9, this novel and highly persistent form of Transgenerational Epigenetic Inheritance could be relevant to human health.