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

Summary Transgenerational Epigenetic Inheritance occurs when gametes transmit forms of information without altering genomic DNA 1 . Although deficiency for telomerase in human families causes transgenerational shortening of telomeres 2 , 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 DNA 3,4 , function in gametes to regulate developmental expression of telomeric foci for multiple generations. C. elegans POT-1 and POT-2 5,6 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 effects 7 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 cancer 8,9 , this novel and highly persistent form of Transgenerational Epigenetic Inheritance could be relevant to human health.