Epigenetic landscapes in wild-type and dimer-mutant Notch regulated T-LL cells. Homo sapiens

NOTCH/RBPJ/MAML ternary transcriptional complex binds to regulatory element and drives gene expression. The complex can function as monomer and dimer. How dimeric complexes regulate gene expression in human cancer is not well studied. Here, we integrate genomic data sets and analyze Notch dimeric complexes-regulated transcriptome and cis-regulatory elements. A subset of coding and non-coding RNA is Notch dimeric complexes-associated. Dimeric complexes recognition sequence enriched in functional dynamic Notch sites and majority of dimer recognition sequence located in (super-)enhancers. Using CRISPR-Cas9-mediated genome editing, we evaluated the function of one dimer-responsive element located in the promoter region of a noncoding RNA NDANR1 and 5' end 16kb away from HES5. Mutation of SPS in this element reduced expression of HES5 and NDANR1. This finding indicates that dimer-responsive elements can function as enhancer for HES5 and at the same time can function as promoter for noncoding RNA NDANR1. Our study reveals the pervasive role of Notch dimeric complexes in transcriptional regulation in human cancer genome. Overall design: Identifying genomic profiles of histone modifications H3K27ac in wild-type Notch (ICN1) and dimer-mutant (R1984A) induced human T-cell acute lymphocytic leukemia cell lines.