RAD21 is the core subunit of the cohesin complex involved in directing genome organization.
Journal
Genome biology
ISSN: 1474-760X
Titre abrégé: Genome Biol
Pays: England
ID NLM: 100960660
Informations de publication
Date de publication:
28 06 2023
28 06 2023
Historique:
received:
20
03
2022
accepted:
07
06
2023
medline:
30
6
2023
pubmed:
29
6
2023
entrez:
28
6
2023
Statut:
epublish
Résumé
The ring-shaped cohesin complex is an important factor for the formation of chromatin loops and topologically associating domains (TADs) by loop extrusion. However, the regulation of association between cohesin and chromatin is poorly understood. In this study, we use super-resolution imaging to reveal the unique role of cohesin subunit RAD21 in cohesin loading and chromatin structure regulation. We directly visualize that up-regulation of RAD21 leads to excessive chromatin loop extrusion into a vermicelli-like morphology with RAD21 clustered into foci and excessively loaded cohesin bow-tying a TAD to form a beads-on-a-string-type pattern. In contrast, up-regulation of the other four cohesin subunits results in even distributions. Mechanistically, we identify that the essential role of RAD21 is attributed to the RAD21-loader interaction, which facilitates the cohesin loading process rather than increasing the abundance of cohesin complex upon up-regulation of RAD21. Furthermore, Hi-C and genomic analysis reveal how RAD21 up-regulation affects genome-wide higher-order chromatin structure. Accumulated contacts are shown at TAD corners while inter-TAD interactions increase after vermicelli formation. Importantly, we find that in breast cancer cells, the expression of RAD21 is aberrantly high with poor patient survival and RAD21 forms beads in the nucleus. Up-regulated RAD21 in HeLa cells leads to compartment switching and up-regulation of cancer-related genes. Our results provide key insights into the molecular mechanism by which RAD21 facilitates the cohesin loading process and provide an explanation to how cohesin and loader work cooperatively to promote chromatin extrusion, which has important implications in construction of three-dimensional genome organization.
Sections du résumé
BACKGROUND
The ring-shaped cohesin complex is an important factor for the formation of chromatin loops and topologically associating domains (TADs) by loop extrusion. However, the regulation of association between cohesin and chromatin is poorly understood. In this study, we use super-resolution imaging to reveal the unique role of cohesin subunit RAD21 in cohesin loading and chromatin structure regulation.
RESULTS
We directly visualize that up-regulation of RAD21 leads to excessive chromatin loop extrusion into a vermicelli-like morphology with RAD21 clustered into foci and excessively loaded cohesin bow-tying a TAD to form a beads-on-a-string-type pattern. In contrast, up-regulation of the other four cohesin subunits results in even distributions. Mechanistically, we identify that the essential role of RAD21 is attributed to the RAD21-loader interaction, which facilitates the cohesin loading process rather than increasing the abundance of cohesin complex upon up-regulation of RAD21. Furthermore, Hi-C and genomic analysis reveal how RAD21 up-regulation affects genome-wide higher-order chromatin structure. Accumulated contacts are shown at TAD corners while inter-TAD interactions increase after vermicelli formation. Importantly, we find that in breast cancer cells, the expression of RAD21 is aberrantly high with poor patient survival and RAD21 forms beads in the nucleus. Up-regulated RAD21 in HeLa cells leads to compartment switching and up-regulation of cancer-related genes.
CONCLUSIONS
Our results provide key insights into the molecular mechanism by which RAD21 facilitates the cohesin loading process and provide an explanation to how cohesin and loader work cooperatively to promote chromatin extrusion, which has important implications in construction of three-dimensional genome organization.
Identifiants
pubmed: 37381036
doi: 10.1186/s13059-023-02982-1
pii: 10.1186/s13059-023-02982-1
pmc: PMC10303866
doi:
Substances chimiques
Cell Cycle Proteins
0
Chromosomal Proteins, Non-Histone
0
Chromatin
0
RAD21 protein, human
0
DNA-Binding Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
155Informations de copyright
© 2023. The Author(s).
Références
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
Mol Cell. 2016 Apr 21;62(2):248-259
pubmed: 26971492
Curr Opin Cell Biol. 2022 Feb;74:13-22
pubmed: 35016058
Genome Biol. 2014;15(12):550
pubmed: 25516281
Cell Oncol (Dordr). 2020 Feb;43(1):1-18
pubmed: 31900901
Mol Cell. 2004 Sep 24;15(6):951-64
pubmed: 15383284
Nature. 2015 Jul 9;523(7559):240-4
pubmed: 26030525
Nature. 2016 Jan 21;529(7586):418-22
pubmed: 26760202
Bioinformatics. 2012 Nov 1;28(21):2843-4
pubmed: 22923296
Science. 2009 Oct 9;326(5950):289-93
pubmed: 19815776
Science. 2019 Dec 13;366(6471):1338-1345
pubmed: 31753851
Cell. 2017 Oct 5;171(2):305-320.e24
pubmed: 28985562
J Recept Signal Transduct Res. 2021 Apr;41(2):145-152
pubmed: 32757700
Proc Natl Acad Sci U S A. 2016 Nov 1;113(44):12444-12449
pubmed: 27791135
Genes Chromosomes Cancer. 2004 Jan;39(1):1-10
pubmed: 14603436
Cell. 2014 Dec 18;159(7):1665-80
pubmed: 25497547
Elife. 2017 Sep 15;6:
pubmed: 28914604
Nature. 2014 Jan 16;505(7483):367-71
pubmed: 24291789
Nat Rev Genet. 2016 Oct 14;17(11):661-678
pubmed: 27739532
Mol Cell. 2020 Sep 17;79(6):917-933.e9
pubmed: 32755595
Cell Rep. 2016 May 31;15(9):2038-49
pubmed: 27210764
EMBO J. 2017 Dec 15;36(24):3600-3618
pubmed: 29217590
Curr Biol. 2006 Aug 8;16(15):1571-8
pubmed: 16890534
Curr Biol. 2004 Sep 7;14(17):1598-603
pubmed: 15341749
NAR Genom Bioinform. 2021 May 22;3(2):lqab040
pubmed: 34046591
Sci Adv. 2021 Feb 10;7(7):
pubmed: 33568486
Breast Cancer Res. 2011 Jan 21;13(1):R9
pubmed: 21255398
EMBO J. 2017 Dec 15;36(24):3573-3599
pubmed: 29217591
Cell. 2017 May 4;169(4):693-707.e14
pubmed: 28475897
Elife. 2017 May 03;6:
pubmed: 28467304
Cell. 1997 Oct 3;91(1):35-45
pubmed: 9335333
Curr Biol. 2006 Dec 19;16(24):2406-17
pubmed: 17112726
Mol Cell. 2023 May 4;83(9):1377-1392.e6
pubmed: 37146570
Cell. 2017 May 18;169(5):930-944.e22
pubmed: 28525758
Annu Rev Genet. 2001;35:673-745
pubmed: 11700297
Cell. 2006 Dec 1;127(5):955-67
pubmed: 17113138
Nat Genet. 2003 Jul;34(3):267-73
pubmed: 12808457
Nature. 2017 Jul 12;547(7662):232-235
pubmed: 28703188
Mol Cancer Ther. 2005 Mar;4(3):361-8
pubmed: 15767545
Science. 2019 Dec 13;366(6471):1345-1349
pubmed: 31780627
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Int J Clin Exp Pathol. 2015 Mar 01;8(3):2909-18
pubmed: 26045799
Genome Biol. 2021 Jul 12;22(1):206
pubmed: 34253239
Cell Rep. 2020 Jan 21;30(3):820-835.e10
pubmed: 31968256
Nature. 2004 Jul 29;430(6999):573-8
pubmed: 15229615
Curr Biol. 2006 May 9;16(9):863-74
pubmed: 16682347
Mol Cell. 2020 Nov 19;80(4):699-711.e7
pubmed: 33091336
Cell Rep. 2015 Aug 4;12(5):719-25
pubmed: 26212329
Genome Biol. 2023 Jun 28;24(1):155
pubmed: 37381036
Bioinformatics. 2020 May 1;36(10):2980-2985
pubmed: 32003791
Curr Protoc Bioinformatics. 2014 Sep 08;47:11.12.1-34
pubmed: 25199790
Cell. 2003 Mar 21;112(6):765-77
pubmed: 12654244
Nucleic Acids Res. 2016 Jul 8;44(W1):W90-7
pubmed: 27141961
Science. 2018 Apr 6;360(6384):102-105
pubmed: 29472443
Nat Genet. 2021 Jan;53(1):100-109
pubmed: 33318687
Nucleic Acids Res. 2012 Dec;40(22):11202-12
pubmed: 23074191
Nature. 2012 Apr 11;485(7398):376-80
pubmed: 22495300
Mol Cell. 2002 Apr;9(4):773-88
pubmed: 11983169
Mol Cell. 2000 Feb;5(2):243-54
pubmed: 10882066
Curr Biol. 2000 Dec 14-28;10(24):1557-64
pubmed: 11137006
Curr Biol. 2003 Nov 11;13(22):1930-40
pubmed: 14614818
Genes (Basel). 2019 Sep 25;10(10):
pubmed: 31557971
Proc Natl Acad Sci U S A. 2020 Jun 30;117(26):15036-15046
pubmed: 32541019
Genome Biol. 2015 Dec 01;16:259
pubmed: 26619908
Science. 2020 Jun 26;368(6498):1454-1459
pubmed: 32409525
Nature. 2013 Sep 26;501(7468):564-8
pubmed: 23975099
Nature. 2017 Nov 2;551(7678):51-56
pubmed: 29094699
Front Oncol. 2020 Sep 04;10:1587
pubmed: 33014808
Trends Genet. 2015 Nov;31(11):651-660
pubmed: 26439501
Oncotarget. 2019 Jul 2;10(42):4307-4320
pubmed: 31303964
Nat Commun. 2020 Aug 7;11(1):3951
pubmed: 32769987