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

Citation:

Severson E, Arnett KL, Wang H, Zang C, Taing L, Liu H, Pear WS, Shirley Liu X, Blacklow SC, Aster JC. Genome-wide identification and characterization of Notch transcription complex-binding sequence-paired sites in leukemia cells. Sci Signal 2017;10(477)

Date Published:

2017 May 02

Abstract:

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.

Last updated on 06/22/2017