Transcription factor cooperativity at a GATA3 tandem DNA sequence determines oncogenic enhancer-mediated activation

Costa, JR; Li, Y; Anuar, NZ; O&#39;Connor, D; Rahman, S; Rapoz-D&#39;Silva, T; Fung, KTM; Pocock, R; Li, Z; Henderson, S; Wang, L; Krulik, ME; Hyseni, S; Singh, N; Morrow, G; Guo, Y; Gresham, DOF; Herrero, J; Jenner, RG; Look, AT; Kappei, D; Mansour, MR

Author(s): Costa, JR; Li, Y; Anuar, NZ; O'Connor, D; Rahman, S; Rapoz-D'Silva, T; Fung, KTM; Pocock, R; Li, Z; Henderson, S; Wang, L; Krulik, ME; Hyseni, S; Singh, N; Morrow, G; Guo, Y; Gresham, DOF; Herrero, J; Jenner, RG; Look, AT; Kappei, D; Mansour, MR;
Details: Publication Year 2025-05-14,Volume 44,Issue #5,Page 115705
Journal Title: Cell Reports
Publication Type: Online publication before print
Abstract: The TAL1 oncogene driving T cell lymphoblastic leukemia is frequently activated through mutated cis-regulatory elements, whereby small insertions or deletions (indels) create a binding site for the transcription factor MYB. Unraveling how non-coding mutations create oncogenic enhancers is key to understanding cancer biology and can provide important insights into fundamental mechanisms of gene regulation. Utilizing a CRISPR-Cas9 screening approach, we identify GATA3 as the key transcriptional regulator of enhancer-mediated TAL1 overexpression. CRISPR-Cas9 engineering of the mutant enhancer reveals a tandem GATA3 site that is required for binding of GATA3, chromatin accessibility, and MYB recruitment. Reciprocally, MYB binding to its motif is required for GATA3 recruitment, consistent with a transcription factor cooperativity model. Importantly, we show that GATA3 stabilizes a TAL1-MYB interaction and that complex formation requires GATA3 binding to DNA. Our work sheds light on the mechanisms of enhancer-mediated oncogene activation, where key transcription factors cooperate to achieve maximal transcriptional output, thereby supporting leukemogenesis.
Keywords: CP: Cancer; CP: Molecular biology; DNA binding domain; Gata3; Myb; T cell acute lymphoblastic leukemia; T-all; Tal1; cooperativity; enhancer; motif; oncogene; transcription factor
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1016/j.celrep.2025.115705
Open Access at Publisher's Site: https://doi.org/10.1016/j.celrep.2025.115705
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-05-27 04:30:50

Last Modified: 2025-05-27 04:31:03