Differential Occupancy and Regulatory Interactions of KDM6A in Bladder Cell Lines
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Published on: June 17, 2020
Gülden Özden-Yılmaz1, Busra Savas1,2, Ahmet Bursalı1
1Izmir Biomedicine and Genome Center, Inciralti, 35340 Izmir, Turkey.
Abstract:
Epigenetic deregulation is a critical theme which needs further investigation in bladder cancer research. One of the most highly mutated genes in bladder cancer is KDM6A, which functions as an H3K27 demethylase and is one of the MLL3/4 complexes. To decipher the role of KDM6A in normal versus tumor settings, we identified the genomic landscape of KDM6A in normal, immortalized, and cancerous bladder cells. Our results showed differential KDM6A occupancy in the genes involved in cell differentiation, chromatin organization, and Notch signaling depending on the cell type and the mutation status of KDM6A. Transcription factor motif analysis revealed HES1 to be enriched at KDM6A peaks identified in the T24 bladder cancer cell line; moreover, it has a truncating mutation in KDM6A and lacks a demethylase domain. Our co-immunoprecipitation experiments revealed TLE co-repressors and HES1 as potential truncated and wild-type KDM6A interactors. With the aid of structural modeling, we explored how truncated KDM6A could interact with TLE and HES1, as well as RUNX and HHEX transcription factors. These structures provide a solid means of studying the functions of KDM6A independently of its demethylase activity. Collectively, our work provides important contributions to the understanding of KDM6A malfunction in bladder cancer.
Insights
Investigating KDM6A in bladder cancer reveals its altered genomic occupancy and interactions with transcription factors like HES1. This study explores KDM6A
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Epigenetic deregulation is crucial in bladder cancer research.
- KDM6A, a highly mutated gene, functions as an H3K27 demethylase within MLL3/4 complexes.
- Understanding KDM6A's role in normal versus tumor cells is essential.
Purpose of the Study:
- To investigate the genomic landscape of KDM6A in normal, immortalized, and cancerous bladder cells.
- To identify KDM6A's interactions with other proteins and transcription factors.
- To explore the structural basis of KDM6A interactions, independent of its demethylase activity.
Main Methods:
- Genomic occupancy profiling of KDM6A.
- Transcription factor motif analysis.
- Co-immunoprecipitation and structural modeling.
Main Results:
- Differential KDM6A occupancy observed in genes related to cell differentiation, chromatin organization, and Notch signaling.
- HES1 identified as enriched at KDM6A peaks in T24 bladder cancer cells.
- TLE co-repressors and HES1 identified as interactors with wild-type and truncated KDM6A.
Conclusions:
- KDM6A malfunction contributes to bladder cancer development.
- Structural modeling provides insights into KDM6A interactions independent of demethylase activity.
- This work advances the understanding of KDM6A's role in bladder cancer.
