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Genome-wide identification and characterization of Notch transcription complex–binding sequence-paired sites in leukemia cells

Paired regulation of protein-coding genes and enhancer noncoding RNAs tunes Notch signaling in leukemia. Paired regulation in Notch signaling The formation of Notch transcription complexes on DNA binding sites called sequence-paired sites (SPSs) adjusts transcriptional responses to Notch signals. However, SPSs are not easily identified by genomic sequencing. Severson et al. developed a method to identify SPSs throughout the genome. In leukemia cells, which often have Notch-activating mutations, SPSs were found in distal regulatory elements (enhancers) as well as proximal elements (promoters) in the chromatin associated with about one-third of Notch target genes. Some SPSs coordinated Notch-dependent coregulation of protein-coding genes and associated “enhancer” noncoding RNAs. The findings highlight the wide range of Notch response elements that exist and presumably “tune” physiologic responses to Notch in normal tissues and mediate pathophysiologic responses to Notch in disease. Notch transcription complexes (NTCs) drive target gene expression by binding to two distinct types of genomic response elements, NTC monomer–binding sites and sequence-paired sites (SPSs) that bind NTC dimers. SPSs are conserved and have been linked to the Notch responsiveness of a few genes. To assess the overall contribution of SPSs to Notch-dependent gene regulation, we determined the DNA sequence requirements for NTC dimerization using a fluorescence resonance energy transfer (FRET) assay and applied insights from these in vitro studies to Notch-“addicted” T cell acute lymphoblastic leukemia (T-ALL) cells. We found that SPSs contributed to the regulation of about a third of direct Notch target genes. Although originally described in promoters, SPSs are present mainly in long-range enhancers, including an enhancer containing a newly described SPS that regulates HES5 expression. Our work provides a general method for identifying SPSs in genome-wide data sets and highlights the widespread role of NTC dimerization in Notch-transformed leukemia cells.