Izmir Biomedicine and Genome Center, Inciralti, 35340 Izmir, Turkey.
Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Inciralti, 35340 Izmir, Turkey.
Cells. 2023 Mar 8;12(6):836. doi: 10.3390/cells12060836.
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 , which functions as an H3K27 demethylase and is one of the MLL3/4 complexes. To decipher the role of in normal versus tumor settings, we identified the genomic landscape of in normal, immortalized, and cancerous bladder cells. Our results showed differential occupancy in the genes involved in cell differentiation, chromatin organization, and Notch signaling depending on the cell type and the mutation status of . Transcription factor motif analysis revealed to be enriched at peaks identified in the T24 bladder cancer cell line; moreover, it has a truncating mutation in and lacks a demethylase domain. Our co-immunoprecipitation experiments revealed co-repressors and as potential truncated and wild-type interactors. With the aid of structural modeling, we explored how truncated could interact with and , as well as and transcription factors. These structures provide a solid means of studying the functions of independently of its demethylase activity. Collectively, our work provides important contributions to the understanding of malfunction in bladder cancer.
表观遗传失调是膀胱癌研究中需要进一步研究的一个关键主题。在膀胱癌中，突变频率最高的基因之一是 ，它作为 H3K27 去甲基酶，是 MLL3/4 复合物之一。为了解析 在正常和肿瘤环境中的作用，我们鉴定了正常、永生化和癌性膀胱细胞中 的基因组景观。我们的结果表明， 在细胞分化、染色质组织和 Notch 信号相关基因上的占有率存在差异，这取决于细胞类型和 的突变状态。转录因子基序分析表明， 在 T24 膀胱癌细胞系中鉴定的 峰中富集；此外， 在 中存在截断突变，并且缺乏去甲基酶结构域。我们的共免疫沉淀实验揭示了 作为潜在的截断和野生型 相互作用因子。借助结构建模，我们探索了截断的 如何与 和 相互作用，以及 和 转录因子相互作用。这些结构为独立于其去甲基酶活性研究 的功能提供了可靠的手段。总之，我们的工作为理解膀胱癌中 的功能失调提供了重要贡献。
