Klosin, AdamReis, Kadri, 1985-Hidalgo-Carcedo, CristinaCasas, EduardVavouri, TanyaLehner, Ben, 1978-2024-02-192024-02-192017Klosin A, Reis K, Hidalgo-Carcedo C, Casas E, Vavouri T, Lehner B. Impaired DNA replication derepresses chromatin and generates a transgenerationally inherited epigenetic memory. Sci Adv. 2017 Aug;3(8):e1701143. DOI: 10.1126/sciadv.17011432375-2548http://hdl.handle.net/10230/59140Includes supplementary materials.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.application/pdfengCopyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.ADNGenomesEmbriologiainfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1126/sciadv.1701143info:eu-repo/semantics/openAccess