3 years ago

Impaired DNA replication derepresses chromatin and generates a transgenerationally inherited epigenetic memory

Cristina Hidalgo-Carcedo, Ben Lehner, Kadri Reis, Eduard Casas, Adam Klosin, Tanya Vavouri

Impaired DNA replication is a hallmark of cancer and a cause of genomic instability. We report that, in addition to causing genetic change, impaired DNA replication during embryonic development can have major epigenetic consequences for a genome. In a genome-wide screen, we identified impaired DNA replication as a cause of increased expression from a repressed transgene in Caenorhabditis elegans. The acquired expression state behaved as an "epiallele," being inherited for multiple generations before fully resetting. Derepression was not restricted to the transgene but was caused by a global reduction in heterochromatin-associated histone modifications due to the impaired retention of modified histones on DNA during replication in the early embryo. Impaired DNA replication during development can therefore globally derepress chromatin, creating new intergenerationally inherited epigenetic expression states.

Publisher URL: http://advances.sciencemag.org/cgi/content/short/3/8/e1701143

DOI: 10.1126/sciadv.1701143

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