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

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.

Source: Signal Transduction Knowledge Environment - May 2, 2017 Category: Science Authors: Severson, E., Arnett, K. L., Wang, H., Zang, C., Taing, L., Liu, H., Pear, W. S., Shirley Liu, X., Blacklow, S. C., Aster, J. C. Tags: STKE Research Articles Source Type: news