Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging.
HIST1H1E
accelerated aging
cellular senescence
chromatin compaction
chromatin dynamics
chromatin remodeling
linker histone
linker histone H1.4
methylation profiling
replicative senescence
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
05 09 2019
05 09 2019
Historique:
received:
06
04
2019
accepted:
10
07
2019
pmc-release:
05
03
2020
pubmed:
27
8
2019
medline:
3
4
2020
entrez:
27
8
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31447100
pii: S0002-9297(19)30270-8
doi: 10.1016/j.ajhg.2019.07.007
pmc: PMC6731364
pii:
doi:
Substances chimiques
Chromatin
0
Histones
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
493-508Subventions
Organisme : NIGMS NIH HHS
ID : T32 GM007748
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Informations de copyright
Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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