Flex, ElisabettaMartinelli, SimoneVan Dijck, AnkeCiolfi, AndreaCecchetti, SerenaColuzzi, ElisaPannone, LucaAndreoli, CristinaRadio, Francesca ClementinaPizzi, SimoneCarpentieri, GiovannaBruselles, AllessandroCatanzaro, GiuseppinaPedace, LuciaMiele, EvelinaCarcarino, ElenaGe, XiaoyanChijiwa, ChiekoLewis, M.E. SuzanneMeuwissen, MarijeKenis, SandraVan der Aa, NathalieLarson, AustinBrown, KathleenWasserstein, Melissa P.Skotko, Brian G.Begtrup, AmberPerson, RichardKarayiorgou, MariaRoos, J.L. (Johannes Louw)Van Gassen, Koen L.Koopmans, MarijeBijlsma, Emilia K.Santen, Gijs W.E.Barge-Schaapveld, Daniela Q.C.M.Ruivenkamp, Claudia A.L.Hoffer, Mariette J.V.Lalani, Seema R.Streff, HaleyCraigen, William J.Graham, Brett H.Van den Elzen, Annette P.M.Kamphuis, Daan J.Ounap, KatrinReinson, KaritPajusalu, SanderWojcik, Monica H.Viberti, ClaraDi Gaetano, CorneliaBertini, EnricoPetrucci, SimonaDe Luca, AlessandroRota, RossellaFerretti, ElisabettaMatullo, GiuseppeDallapiccola, BrunoSgura, AntonellaWalkiewicz, MagdalenaKooy, R. FrankTartaglia, Marco2019-09-302019-09Flex, E., Martinelli, S., Van Dijck, A. et al. 2019, 'Aberrant function of the C-terminal tail of HIST1H1E accelerates cellular senescence and causes premature aging', American Journal of Human Genetics, vol. 105, no. 3, pp. 493-508.0002-9297 (print)1537-6605 (online)10.1016/j.ajhg.2019.07.007http://hdl.handle.net/2263/71488Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.en© 2019 by The American Society of Human Genetics. All rights reserved. Notice : this is the author’s version of a work that was accepted for publication in American Journal of Human Genetics. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. A definitive version was subsequently published in American Journal of Human Genetics, vol. 105, no. 3, pp. 493-508, 2019. doi : 10.1016/j.ajhg.2019.07.007.Linker histoneHIST1H1ELinker histone H1.4Cellular senescenceReplicative senescenceAccelerated agingChromatin compactionChromatin remodelingChromatin dynamicsMethylation profilingPostprint Article