Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging

Elisabetta Flex, Simone Martinelli, Anke Van Dijck, Andrea Ciolfi, Serena Cecchetti, Elisa Coluzzi, Luca Pannone, Cristina Andreoli, Francesca Clementina Radio, Simone Pizzi, Giovanna Carpentieri, Alessandro Bruselles, Giuseppina Catanzaro, Lucia Pedace, Evelina Miele, Elena Carcarino, Xiaoyan Ge, Chieko Chijiwa, Me Suzanne Lewis, Marije MeuwissenSandra Kenis, Nathalie Van der Aa, Austin Larson, Kathleen Brown, Melissa P. Wasserstein, Brian G. Skotko, Amber Begtrup, Richard Person, Maria Karayiorgou, J. Louw Roos, Koen L. Van Gassen, Marije Koopmans, Emilia K. Bijlsma, Gijs W. E. Santen, Daniela Q. C. M. Barge-Schaapveld, Claudia A. L. Ruivenkamp, Mariette J. Hoffer V, Seema R. Lalani, Haley Streff, William J. Craigen, Brett H. Graham, Annette P. M. van den Elzen, Daan J. Kamphuis, Enrico Bertini, Simona Petrucci, Alessandro De Luca, Rossella Rota, Elisabetta Ferretti, Bruno Dallapiccola, Marco Tartaglia

Research output: Contribution to journalArticle

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.
Original languageUndefined/Unknown
Pages (from-to)493-508
Number of pages16
JournalAmerican Journal of Human Genetics
Volume105
Issue number3
DOIs
Publication statusPublished - Sep 5 2019

Cite this

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. S., ... Tartaglia, M. (2019). Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging. American Journal of Human Genetics, 105(3), 493-508. https://doi.org/10.1016/j.ajhg.2019.07.007