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Truncated KDM6A exhibits differential chromatin occupancy and regulatory interactions

ABSTRACT: Genome-wide studies characterizing mutational landscape of bladder cancer revealed the exceptionally high rate of chromatin modifier genes in bladder cancer. Thus, epigenetic deregulation is a critical theme which needs further investigation for bladder cancer research. One of the highly mutated genes in bladder cancer is KDM6A, functioning as H3K27 demethylase and part of MLL3/4 complexes. To decipher the role of KDM6A in normal vs tumor setting, we identified the genomic localization profiles of KDM6A in normal, immortalized and cancer bladder cells. Our results showed differential occupancy of KDM6A at 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 an enrichment for HES1 for the KDM6A peaks identified for T24 bladder cancer cell line, which has a truncating mutation in KDM6A and lacking demethylase domain and also for the other clusters showing KDM6A localization. For the first time, using co-immunoprecipitation experiments, we show that KDM6A is in complex with TLE co-repressors and HES1, and illustrate the potential interaction of KDM6A with TLE co-repressors, HES1, RUNX, HHEX transcription factors by computational structural biology models. Our work makes important contributions to the understanding of KDM6A malfunction in bladder cancer and provides models for the functioning of KDM6A independent of its demethylase activity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE216625 | GEO | 2023/03/03

REPOSITORIES: GEO

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