ZKSCAN3 counteracts cellular senescence by stabilizing heterochromatin.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
19 06 2020
19 06 2020
Historique:
accepted:
08
05
2020
revised:
13
04
2020
received:
12
03
2020
pubmed:
20
5
2020
medline:
9
9
2020
entrez:
20
5
2020
Statut:
ppublish
Résumé
Zinc finger protein with KRAB and SCAN domains 3 (ZKSCAN3) has long been known as a master transcriptional repressor of autophagy. Here, we identify a novel role for ZKSCAN3 in alleviating senescence that is independent of its autophagy-related activity. Downregulation of ZKSCAN3 is observed in aged human mesenchymal stem cells (hMSCs) and depletion of ZKSCAN3 accelerates senescence of these cells. Mechanistically, ZKSCAN3 maintains heterochromatin stability via interaction with heterochromatin-associated proteins and nuclear lamina proteins. Further study shows that ZKSCAN3 deficiency results in the detachment of genomic lamina-associated domains (LADs) from the nuclear lamina, loss of heterochromatin, a more accessible chromatin status and consequently, aberrant transcription of repetitive sequences. Overexpression of ZKSCAN3 not only rescues premature senescence phenotypes in ZKSCAN3-deficient hMSCs but also rejuvenates physiologically and pathologically senescent hMSCs. Together, these data reveal for the first time that ZKSCAN3 functions as an epigenetic modulator to maintain heterochromatin organization and thereby attenuate cellular senescence. Our findings establish a new functional link among ZKSCAN3, epigenetic regulation, and stem cell aging.
Identifiants
pubmed: 32427330
pii: 5840577
doi: 10.1093/nar/gkaa425
pmc: PMC7293006
doi:
Substances chimiques
Heterochromatin
0
Transcription Factors
0
ZKSCAN3 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6001-6018Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
Epigenetics Chromatin. 2018 Feb 26;11(1):7
pubmed: 29482634
Chromosome Res. 2017 Mar;25(1):77-87
pubmed: 28078514
Cancer Sci. 2017 Apr;108(4):563-569
pubmed: 28165648
Oncogene. 2011 Mar 17;30(11):1329-40
pubmed: 21057542
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Nature. 2014 Dec 11;516(7530):242-5
pubmed: 25274305
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
Cell Res. 2016 Feb;26(2):190-205
pubmed: 26768768
Cell. 2015 Sep 24;163(1):30-2
pubmed: 26406368
Cell Rep. 2018 Jun 5;23(10):2874-2880
pubmed: 29874575
J Exp Med. 2017 Oct 2;214(10):3123-3144
pubmed: 28904110
Aging Cell. 2013 Apr;12(2):247-56
pubmed: 23360310
Cell. 2013 Jun 6;153(6):1194-217
pubmed: 23746838
Cell Rep. 2019 Jun 11;27(11):3215-3227.e6
pubmed: 31189106
Nucleic Acids Res. 2016 Jul 8;44(W1):W160-5
pubmed: 27079975
Cell Metab. 2017 Sep 5;26(3):460-474
pubmed: 28826795
Nature. 2015 Jan 29;517(7536):583-8
pubmed: 25494202
PLoS Genet. 2017 Aug 31;13(8):e1006879
pubmed: 28859074
Nature. 2012 Jan 04;481(7381):389-93
pubmed: 22217937
Cell. 2013 Jan 31;152(3):584-98
pubmed: 23374351
Mob DNA. 2016 May 06;7:9
pubmed: 27158268
Proc Natl Acad Sci U S A. 1994 May 10;91(10):4514-8
pubmed: 8183940
Genome Res. 2017 Oct;27(10):1634-1644
pubmed: 28916540
Nat Rev Mol Cell Biol. 2020 Mar;21(3):137-150
pubmed: 32020082
Cell Rep. 2019 Mar 26;26(13):3643-3656.e7
pubmed: 30917318
Genome Biol. 2014;15(12):550
pubmed: 25516281
Dev Cell. 2016 Mar 21;36(6):611-23
pubmed: 27003935
Aging (Albany NY). 2017 Mar 12;9(3):803-822
pubmed: 28288000
Cell Stem Cell. 2011 Jan 7;8(1):31-45
pubmed: 21185252
Exp Neurobiol. 2019 Dec 31;28(6):643-657
pubmed: 31902153
Epigenetics. 2013 Mar;8(3):317-32
pubmed: 23417056
Autophagy. 2013 May;9(5):808-12
pubmed: 23422284
Science. 2015 Jun 5;348(6239):1160-3
pubmed: 25931448
Aging (Albany NY). 2013 Dec;5(12):867-83
pubmed: 24323947
PLoS Biol. 2019 Apr 1;17(4):e3000201
pubmed: 30933975
Autophagy. 2019 Apr;15(4):631-651
pubmed: 30335591
Life Sci. 2007 Sep 15;81(14):1141-51
pubmed: 17868742
Science. 2019 Feb 15;363(6428):
pubmed: 30765536
PLoS Genet. 2012 Jan;8(1):e1002473
pubmed: 22291607
Nature. 2019 Feb;566(7742):73-78
pubmed: 30728521
Sci Immunol. 2017 Feb;2(8):
pubmed: 28439570
Curr Opin Genet Dev. 2003 Dec;13(6):651-8
pubmed: 14638329
Genome Res. 2007 Sep;17(9):1245-53
pubmed: 17690206
Cell. 2018 Jul 12;174(2):406-421.e25
pubmed: 29887375
Nat Protoc. 2007;2(6):1467-78
pubmed: 17545983
Nat Protoc. 2017 Apr;12(4):828-863
pubmed: 28333914
Science. 2014 Dec 5;346(6214):1187-8
pubmed: 25477445
Development. 2017 Aug 1;144(15):2719-2729
pubmed: 28765213
Int J Biochem Cell Biol. 2012 Jul;44(7):1166-73
pubmed: 22531714
Nature. 2019 Sep;573(7773):281-286
pubmed: 31485078
Genome Biol. 2008;9(9):R137
pubmed: 18798982
Mol Cell. 2010 May 28;38(4):576-89
pubmed: 20513432
Nat Methods. 2012 Feb 28;9(3):215-6
pubmed: 22373907
Protein Cell. 2019 Oct;10(10):770-775
pubmed: 31325157
Protein Cell. 2019 Sep;10(9):649-667
pubmed: 30796637
Bioinformatics. 2009 Aug 1;25(15):1952-8
pubmed: 19505939
Cell Res. 2017 Sep;27(9):1178-1181
pubmed: 28685772
Trends Genet. 2007 Apr;23(4):183-91
pubmed: 17331616
Protein Cell. 2018 Nov;9(11):945-965
pubmed: 29968158
Anticancer Res. 2016 May;36(5):2397-406
pubmed: 27127149
Cell Discov. 2018 Jan 5;4:2
pubmed: 29423270
Cell. 2020 Mar 5;180(5):984-1001.e22
pubmed: 32109414
Genome Biol. 2003;4(10):231
pubmed: 14519192
Cell. 2017 May 18;169(5):780-791
pubmed: 28525751
Nat Methods. 2015 Apr;12(4):357-60
pubmed: 25751142
Mol Cell. 2013 Apr 11;50(1):16-28
pubmed: 23434374
Cell. 2016 Jun 2;165(6):1361-1374
pubmed: 27259148
Science. 2011 Jun 17;332(6036):1429-33
pubmed: 21617040
Cell Metab. 2019 Apr 2;29(4):871-885.e5
pubmed: 30853213
Autophagy. 2017 Jul 3;13(7):1235-1238
pubmed: 28581889
Cell Stem Cell. 2019 Mar 7;24(3):447-461.e8
pubmed: 30661960
Bioinformatics. 2010 Mar 15;26(6):841-2
pubmed: 20110278
Protein Cell. 2016 Jul;7(7):478-88
pubmed: 27271327
Protein Cell. 2020 Jan;11(1):1-22
pubmed: 31037510
Genome Res. 2012 Oct;22(10):1995-2007
pubmed: 22637570
Protein Cell. 2019 Nov;10(11):846-853
pubmed: 31642032
Gene. 2015 Mar 10;558(2):187-94
pubmed: 25617522
Biochemistry (Mosc). 2017 Aug;82(8):962-971
pubmed: 28941465
Oncotarget. 2016 Aug 16;7(33):53599-53610
pubmed: 27447553
EMBO Rep. 2015 May;16(5):610-7
pubmed: 25784758
Nat Commun. 2019 Jul 26;10(1):3329
pubmed: 31350386
Protein Cell. 2018 Apr;9(4):333-350
pubmed: 29476423
Exp Gerontol. 1997 Jul-Oct;32(4-5):383-94
pubmed: 9315443
Nucleic Acids Res. 2009 Jul;37(Web Server issue):W305-11
pubmed: 19465376
Microbiol Spectr. 2015 Feb;3(1):MDNA3-0009-2014
pubmed: 26104559
Cell Rep. 2014 Nov 6;9(3):1163-70
pubmed: 25437568
Cancer Res. 2008 Jun 1;68(11):4321-30
pubmed: 18519692
Nature. 2016 Dec 1;540(7631):144-149
pubmed: 27851729