A stem cell marker KLF5 regulates CCAT1 via three-dimensional genome structure in colorectal cancer cells
Menée à l'aide d'échantillons tumoraux prélevés sur des patients atteints d'un cancer colorectal, cette étude met en évidence un mécanisme par lequel le facteur de transcription KLF5 régule l'expression du gène CCAT1 via une structure génomique tridimensionnelle comportant le site de démarrage de la transcription de CCAT1 ainsi que le promoteur et la région amplificatrice du gène codant pour KLF5
Background : KLF5 plays a crucial role in stem cells of colorectum in cooperation with Lgr5 gene. In this study, we aimed to explicate a regulatory mechanism of the KLF5 gene product from a view of three-dimensional genome structure in colorectal cancer (CRC). Methods : In vitro engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP)-seq method was used to identify the regions that bind to the KLF5 promoter. Results : We revealed that the KLF5 promoter region interacted with the KLF5 enhancer region as well as the transcription start site (TSS) region of the Colon Cancer Associated Transcript 1 (CCAT1) gene. Notably, the heterodeletion mutants of KLF5 enhancer impaired the cancer stem-like properties of CRC cells. The KLF5 protein participated in the core-regulatory circuitry together with co-factors (BRD4, MED1, and RAD21), which constructs the three-dimensional genome structures consisting of KLF5 promoter, enhancer and CCAT1 TSS region. In vitro analysis indicated that KLF5 regulated CCAT1 expression and we found that CCAT1 expression was highly correlated with KLF5 expression in CRC clinical samples. Conclusions : Our data propose the mechanistic insight that the KLF5 protein constructs the core-regulatory circuitry with co-factors in the three-dimensional genome structure and coordinately regulates KLF5 and CCAT1 expression in CRC.