STAG2 loss-of-function affects short-range genomic contacts and modulates the basal-luminal transcriptional program of bladder cancer cells.
Base Sequence
Cell Cycle Proteins
/ antagonists & inhibitors
Cell Line, Tumor
Chromatin
/ chemistry
Chromosomal Proteins, Non-Histone
/ genetics
DNA, Neoplasm
/ genetics
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Gene Ontology
HEK293 Cells
Histones
/ genetics
Humans
Loss of Function Mutation
Molecular Sequence Annotation
Nuclear Proteins
/ genetics
RNA, Small Interfering
/ genetics
Signal Transduction
Transcription, Genetic
Urinary Bladder Neoplasms
/ genetics
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
08 11 2021
08 11 2021
Historique:
accepted:
29
09
2021
revised:
08
09
2021
received:
05
02
2021
pubmed:
15
10
2021
medline:
24
12
2021
entrez:
14
10
2021
Statut:
ppublish
Résumé
Cohesin exists in two variants containing STAG1 or STAG2. STAG2 is one of the most mutated genes in cancer and a major bladder tumor suppressor. Little is known about how its inactivation contributes to tumorigenesis. Here, we analyze the genomic distribution of STAG1 and STAG2 and perform STAG2 loss-of-function experiments using RT112 bladder cancer cells; we then analyze the genomic effects by integrating gene expression and chromatin interaction data. Functional compartmentalization exists between the cohesin complexes: cohesin-STAG2 displays a distinctive genomic distribution and mediates short and mid-ranged interactions that engage genes at higher frequency than those established by cohesin-STAG1. STAG2 knockdown results in down-regulation of the luminal urothelial signature and up-regulation of the basal transcriptional program, mirroring differences between STAG2-high and STAG2-low human bladder tumors. This is accompanied by rewiring of DNA contacts within topological domains, while compartments and domain boundaries remain refractive. Contacts lost upon depletion of STAG2 are assortative, preferentially occur within silent chromatin domains, and are associated with de-repression of lineage-specifying genes. Our findings indicate that STAG2 participates in the DNA looping that keeps the basal transcriptional program silent and thus sustains the luminal program. This mechanism may contribute to the tumor suppressor function of STAG2 in the urothelium.
Identifiants
pubmed: 34648034
pii: 6396892
doi: 10.1093/nar/gkab864
pmc: PMC8565347
doi:
Substances chimiques
Cell Cycle Proteins
0
Chromatin
0
Chromosomal Proteins, Non-Histone
0
DNA, Neoplasm
0
Histones
0
Nuclear Proteins
0
RNA, Small Interfering
0
STAG1 protein, human
0
STAG2 protein, human
0
structural maintenance of chromosome protein 1
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
11005-11021Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
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