Oncogenic transcription factors instruct promoter-enhancer hubs in individual triple negative breast cancer cells
Menée à l'aide de modèles cellulaires de cancer du sein triple négatif ainsi que d'une approche combinant analyse génomique et cartographie optique, cette étude met en évidence un mécanisme par lequel des facteurs de transcription oncogènes, en contrôlant la formation d'assemblages topologiques facilitant les interactions entre promoteurs et séquences amplificatrices, favorise l'expression aberrante de gènes dans les cellules cancéreuses
Sequencing-based mapping of ensemble pairwise interactions among regulatory elements support the existence of topological assemblies known as promoter-enhancer hubs or cliques in cancer. Yet, prevalence, regulators, and functions of promoter-enhancer hubs in individual cancer cells remain unclear. Here, we systematically integrated functional genomics, transcription factor screening, and optical mapping of promoter-enhancer interactions to identify key promoter-enhancer hubs, examine heterogeneity of their assembly, determine their regulators, and elucidate their role in gene expression control in individual triple negative breast cancer (TNBC) cells. Optical mapping of individual SOX9 and MYC alleles revealed the existence of frequent multiway interactions among promoters and enhancers within spatial hubs. Our single-allele studies further demonstrated that lineage-determining SOX9 and signaling-dependent NOTCH1 transcription factors compact MYC and SOX9 hubs. Together, our findings suggest that promoter-enhancer hubs are dynamic and heterogeneous topological assemblies, which are controlled by oncogenic transcription factors and facilitate subtype-restricted gene expression in cancer. Optical mapping of single alleles in TNBC revealed the existence of frequent multiway interactions among promoters and enhancers.
Science Advances , article en libre accès, 2023