Kasa invazif olan ve olmayan mesane kanserihücre hatlarını karakterize eden transkripsyonel regülasyon ağlarının belirlenmesi

Bladder cancer is divided into muscle invasive and non-muscle invasive bladder cancer (MIBC and NMIBC) histopathologically however their prognosis and treatment options are different. In this thesis, the transcriptional regulatory mechanisms characterizing MIBC and NMIBC are aimed to be identified. H3K27ac chromatin immunoprecipitation followed by sequencing (ChIP-Seq) was used to identify group specific enhancers specific to MIBC (5637, HT1376, J82, T24) and NMIBC (RT112, RT4) cell lines. Transcription factor motifs on differential active regulatory regions are identified and possible gene targets were found. Selective Isolation of Chromatin Associated Proteins (ChIP-SICAP) method was used to find co-partner proteins of the transcription factors. FLI1 and FRA1 ChIP-Seq experiments are also done and the target genes were filtered accordingly. Finally, knockdown of the transcription factors characterizing MIBC group was performed. FLI1 and FRA1 transcription factors are determined to be enriched at MIBC specific enhancers and GRHL2, Tp63 and PPARg transcription factors are found at NMIBC specific enhancers. Predicted target genes of MIBC group were mostly involved "epithelial cell migration" however NMIBC group's target genes are mainly consisting transcription factors. Integrative analysis of FLI1 and FRA1 ChIP-SICAP and ChIP-Seq and FLI1 and FRA1 knockdown experiments showed that MAP4K4 and FLOT1 genes are the two key target genes regulated by these transcription factors. Collectively our results uncovered the regulatory landscapes characterizing MIBC and NMIBC. FLI1 and FRA1 are determined as the two prominent transcription factors regulating the genes involved in gain of invasive characteristics. Key Words: Bladder cancer, epigenetics, gene regulation, invasion