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


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.

SUBMITTER: Flex E 

PROVIDER: S-EPMC6731364 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Flex Elisabetta E   Martinelli Simone S   Van Dijck Anke A   Ciolfi Andrea A   Cecchetti Serena S   Coluzzi Elisa E   Pannone Luca L   Andreoli Cristina C   Radio Francesca Clementina FC   Pizzi Simone S   Carpentieri Giovanna G   Bruselles Alessandro A   Catanzaro Giuseppina G   Pedace Lucia L   Miele Evelina E   Carcarino Elena E   Ge Xiaoyan X   Chijiwa Chieko C   Lewis M E Suzanne MES   Meuwissen Marije M   Kenis Sandra S   Van der Aa Nathalie N   Larson Austin A   Brown Kathleen K   Wasserstein Melissa P MP   Skotko Brian G BG   Begtrup Amber A   Person Richard R   Karayiorgou Maria M   Roos J Louw JL   Van Gassen Koen L KL   Koopmans Marije M   Bijlsma Emilia K EK   Santen Gijs W E GWE   Barge-Schaapveld Daniela Q C M DQCM   Ruivenkamp Claudia A L CAL   Hoffer Mariette J V MJV   Lalani Seema R SR   Streff Haley H   Craigen William J WJ   Graham Brett H BH   van den Elzen Annette P M APM   Kamphuis Daan J DJ   Õunap Katrin K   Reinson Karit K   Pajusalu Sander S   Wojcik Monica H MH   Viberti Clara C   Di Gaetano Cornelia C   Bertini Enrico E   Petrucci Simona S   De Luca Alessandro A   Rota Rossella R   Ferretti Elisabetta E   Matullo Giuseppe G   Dallapiccola Bruno B   Sgura Antonella A   Walkiewicz Magdalena M   Kooy R Frank RF   Tartaglia Marco M  

American journal of human genetics 20190822 3


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 ult  ...[more]

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