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.

journal_name

Am J Hum Genet

authors

Flex E,Martinelli S,Van Dijck A,Ciolfi A,Cecchetti S,Coluzzi E,Pannone L,Andreoli C,Radio FC,Pizzi S,Carpentieri G,Bruselles A,Catanzaro G,Pedace L,Miele E,Carcarino E,Ge X,Chijiwa C,Lewis MES,Meuwissen M,Kenis S

doi

10.1016/j.ajhg.2019.07.007

subject

Has Abstract

pub_date

2019-09-05 00:00:00

pages

493-508

issue

3

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(19)30270-8

journal_volume

105

pub_type

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