GSE116869
Oncogenic Notch promotes long-range regulatory interactions within hyperconnected 3D cliques [MB157_HiChIP]
Purpose: To investigate the impact of oncogenic Notch on the 3D genome organization of cancer cells. Methods: We generated cohesin HiChIP and 1D epigenomic data sets in two different Notch-dependent cancer cell types, triple-negative breast cancer (TNBC) and mantle cell lymphoma (MCL), in the Notch-on and -off states. Results: We report here that Notch transcription complexes control their direct target genes through two distinct regulatory modes: either through existing loops or by facilitating new long-range regulatory interactions. This combination of pre-existing and Notch-promoted loops coalesce enhancers and promoters to form highly interacting clusters, termed “3D cliques”. Notch preferentially activates enhancers and promotes looping interactions within highly connected 3D cliques that regulate key oncogenes. Conclusions: These observations suggest a general mechanism that oncogenic transcription factors can exploit to regulate the transcriptional outputs of cancer cells. Overall design: ChIP-seq, RNA-seq and HiChIP in Notch-on, -off, -recovery conditions in TNBC and MCL cell lines to profile Notch transcriptional complex binding, histone modification, Notch target genes and contact between regulatory elements.