期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 105, 期 3, 页码 493-508出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2019.07.007
关键词
-
资金
- Fondazione Bambino Gesu (Vite Coraggiose)
- Italian Ministry of Health
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG21390, IG21614]
- Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR) Dipartimenti di Eccellenza (miur) [D15D18000410001]
- National Human Genome Research Institute [UM1 HG008900]
- National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program
- National Eye Institute
- National Institutes of Health (NIH) [T32GM007748]
- European Research Area Network (ERA-NET) NEURONthrough the Research Foundation-Flanders (FWO)
- Estonian Research Council [PRG471, PUTJD827]
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据