Aberrant function of the C-terminal tail of HIST1H1E accelerates cellular senescence and causes premature aging

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Authors

Flex, Elisabetta
Martinelli, Simone
Van Dijck, Anke
Ciolfi, Andrea
Cecchetti, Serena
Coluzzi, Elisa
Pannone, Luca
Andreoli, Cristina
Radio, Francesca Clementina
Pizzi, Simone

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Elsevier

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.

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Keywords

Linker histone, HIST1H1E, Linker histone H1.4, Cellular senescence, Replicative senescence, Accelerated aging, Chromatin compaction, Chromatin remodeling, Chromatin dynamics, Methylation profiling

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Citation

Flex, 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.