Model depicting the genome-scale actions of T-cell factor 1 (Tcf1) in promoting chromatin accessibility for T-cell development and leukemogenesis. Physiological Notch signaling directs Tcf1 to displace nucleosomes, paving the way for additional transcription factors to bind and induce T-cell differentiation genes. In contrast, supraphysiological Notch signaling directs Tcf1 to open a newly appreciated myelocytomatosis protooncogene (Myc) enhancer (TMe) that transforms Notch actions from physiological to oncogenic. HSC, hematopoietic stem cell. See the visual abstract in the article by Antoszewski et al that begins on page 2483.