SIRT3 consolidates heterochromatin and counteracts senescence.
Aging
/ genetics
Animals
CRISPR-Associated Protein 9
CRISPR-Cas Systems
Cells, Cultured
Cellular Senescence
/ genetics
Gene Knockout Techniques
HEK293 Cells
Heterochromatin
/ genetics
Humans
Male
Mesenchymal Stem Cells
/ metabolism
Mice
Mice, Nude
Mice, SCID
Nuclear Envelope
/ metabolism
Protein Domains
Sirtuin 3
/ chemistry
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
07 05 2021
07 05 2021
Historique:
accepted:
01
03
2021
revised:
09
02
2021
received:
06
01
2021
pubmed:
12
3
2021
medline:
29
5
2021
entrez:
11
3
2021
Statut:
ppublish
Résumé
Sirtuin 3 (SIRT3) is an NAD+-dependent deacetylase linked to a broad range of physiological and pathological processes, including aging and aging-related diseases. However, the role of SIRT3 in regulating human stem cell homeostasis remains unclear. Here we found that SIRT3 expression was downregulated in senescent human mesenchymal stem cells (hMSCs). CRISPR/Cas9-mediated depletion of SIRT3 led to compromised nuclear integrity, loss of heterochromatin and accelerated senescence in hMSCs. Further analysis indicated that SIRT3 interacted with nuclear envelope proteins and heterochromatin-associated proteins. SIRT3 deficiency resulted in the detachment of genomic lamina-associated domains (LADs) from the nuclear lamina, increased chromatin accessibility and aberrant repetitive sequence transcription. The re-introduction of SIRT3 rescued the disorganized heterochromatin and the senescence phenotypes. Taken together, our study reveals a novel role for SIRT3 in stabilizing heterochromatin and counteracting hMSC senescence, providing new potential therapeutic targets to ameliorate aging-related diseases.
Identifiants
pubmed: 33706382
pii: 6168313
doi: 10.1093/nar/gkab161
pmc: PMC8096253
doi:
Substances chimiques
Heterochromatin
0
CRISPR-Associated Protein 9
EC 3.1.-
SIRT3 protein, human
EC 3.5.1.-
Sirtuin 3
EC 3.5.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4203-4219Commentaires et corrections
Type : ErratumIn
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
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