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Updated: Oct 16, 2025
An Orthotopic Bladder Cancer Model for Gene Delivery Studies
Published on: December 1, 2013
STAG2 loss-of-function affects short-range genomic contacts and modulates the basal-luminal transcriptional program
Laia Richart1, Eleonora Lapi1,2, Vera Pancaldi3,4,5
1Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
Abstract:
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.
Insights
Loss of the STAG2 protein, a key component of cohesin, disrupts DNA looping in bladder cancer cells. This disruption silences basal gene programs, potentially explaining STAG2's tumor suppressor role in urothelial cancers.
Area of Science:
- Cellular biology
- Genomics
- Cancer research
Background:
- Cohesin is a protein complex crucial for genome organization, existing in variants with STAG1 or STAG2.
- STAG2 is frequently mutated in cancers, particularly bladder cancer, and acts as a tumor suppressor.
- The precise mechanisms by which STAG2 inactivation drives tumorigenesis remain largely unknown.
Purpose of the Study:
- To investigate the distinct genomic roles of cohesin variants containing STAG1 versus STAG2.
- To elucidate the functional consequences of STAG2 loss-of-function in bladder cancer.
- To understand how STAG2 contributes to maintaining urothelial cell identity and suppresses tumor formation.
Main Methods:
- Analysis of STAG1 and STAG2 genomic distribution.
- STAG2 loss-of-function experiments in RT112 bladder cancer cells.
- Integration of gene expression and chromatin interaction data (Hi-C).
Main Results:
- Cohesin-STAG2 exhibits a unique genomic distribution, mediating shorter-range DNA interactions compared to cohesin-STAG1.
- STAG2 depletion alters gene expression, downregulating luminal urothelial markers and upregulating basal programs, mirroring human bladder tumors.
- Loss of STAG2 leads to rewiring of DNA contacts within topological domains, affecting silent chromatin and de-repressing lineage genes.
Conclusions:
- STAG2 is essential for maintaining urothelial cell identity by silencing basal transcriptional programs through DNA looping.
- STAG2 inactivation disrupts this mechanism, potentially contributing to bladder tumorigenesis.
- Understanding STAG2's role offers insights into its tumor suppressor function and potential therapeutic strategies.
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