1. Aberrant function of the C-terminal tail of HIST1H1E Aacelerates cellular senescence and causes premature aging
- Author
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Giuseppe Matullo, Brett H. Graham, Elisa Coluzzi, Karit Reinson, Antonella Sgura, Monica H. Wojcik, Luca Pannone, Melissa P. Wasserstein, Lucia Pedace, Seema R. Lalani, Elena Carcarino, Daniela Q.C.M. Barge-Schaapveld, Anke Van Dijck, Austin Larson, Giovanna Carpentieri, Alessandro Bruselles, Simona Petrucci, Simone Pizzi, Elisabetta Flex, Cornelia Di Gaetano, Francesca Clementina Radio, Bruno Dallapiccola, Serena Cecchetti, Clara Viberti, Enrico Bertini, Chieko Chijiwa, Emilia K. Bijlsma, Elisabetta Ferretti, William J. Craigen, Cristina Andreoli, Brian G. Skotko, Daan J. Kamphuis, Alessandro De Luca, J. Louw Roos, Giuseppina Catanzaro, Sandra Kenis, Mariëtte J.V. Hoffer, Katrin Õunap, Maria Karayiorgou, Gijs W. E. Santen, Annette P.M. van den Elzen, Kathleen Brown, Haley Streff, M. E. Suzanne Lewis, Claudia A. L. Ruivenkamp, Xiaoyan Ge, Andrea Ciolfi, Nathalie Van der Aa, Marco Tartaglia, Rossella Rota, Amber Begtrup, Richard E. Person, Simone Martinelli, Koen L.I. van Gassen, R. Frank Kooy, Marije Meuwissen, Magdalena Walkiewicz, Evelina Miele, Marije Koopmans, Sander Pajusalu, Flex, E., Martinelli, S., Van Dijck, A., Ciolfi, A., Cecchetti, S., Coluzzi, E., Pannone, L., Andreoli, C., Radio, F. C., Pizzi, S., Carpentieri, G., Bruselles, A., Catanzaro, G., Pedace, L., Miele, E., Carcarino, E., Ge, X., Chijiwa, C., Lewis, M. E. S., Meuwissen, M., Kenis, S., Van der Aa, N., Larson, A., Brown, K., Wasserstein, M. P., Skotko, B. G., Begtrup, A., Person, R., Karayiorgou, M., Roos, J. L., Van Gassen, K. L., Koopmans, M., Bijlsma, E. K., Santen, G. W. E., Barge-Schaapveld, D. Q. C. M., Ruivenkamp, C. A. L., Hoffer, M. J. V., Lalani, S. R., Streff, H., Craigen, W. J., Graham, B. H., van den Elzen, A. P. M., Kamphuis, D. J., Ounap, K., Reinson, K., Pajusalu, S., Wojcik, M. H., Viberti, C., Di Gaetano, C., Bertini, E., Petrucci, S., De Luca, A., Rota, R., Ferretti, E., Matullo, G., Dallapiccola, B., Sgura, A., Walkiewicz, M., Kooy, R. F., and Tartaglia, M.
- Subjects
0301 basic medicine ,Premature aging ,Senescence ,Male ,Cell division ,methylation profiling ,Article ,Chromatin remodeling ,chromatin remodeling ,Histones ,03 medical and health sciences ,chemistry.chemical_compound ,replicative senescence ,0302 clinical medicine ,HIST1H1E ,chromatin dynamic ,Genetics ,accelerated aging ,cellular senescence ,Humans ,Genetics(clinical) ,Child ,Biology ,Genetics (clinical) ,chromatin compaction ,chromatin dynamics ,linker histone ,linker histone H1.4 ,Aneuploidy ,Cell Nucleolus ,Cellular Senescence ,Chromatin ,DNA Methylation ,Female ,Infant ,Middle Aged ,biology ,DNA replication ,Cell biology ,030104 developmental biology ,Histone ,chemistry ,biology.protein ,Human medicine ,030217 neurology & neurosurgery ,DNA - Abstract
Histones 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.
- Published
- 2019