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

Joana R Costa¹, Yang Li¹, Nurkaiyisah Zaal Anuar², David O'Connor³, Sunniyat Rahman⁴, Tanya Rapoz-D'Silva¹, Kent T M Fung¹, Rachael Pocock¹, Zhaodong Li⁵, Stephen Henderson⁶, Lingyi Wang⁷, Mateja E Krulik⁸, Sara Hyseni¹, Nivedita Singh⁹, George Morrow¹⁰, Yanping Guo¹⁰, Daisy O F Gresham⁷, Javier Herrero⁶, Richard G Jenner¹¹, A Thomas Look¹², Dennis Kappei¹³, Marc R Mansour¹⁴

Affiliations

¹ Department of Haematology, UCL Cancer Institute, University College London, London, UK.
² Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
³ Department of Haematology, UCL Cancer Institute, University College London, London, UK; Department of Haematology, Great Ormond Street Hospital for Children, London, UK.
⁴ Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
⁵ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁶ Cancer Institute Bioinformatics Hub, UCL Cancer Institute, University College London, London, UK; CRUK City of London Centre, UCL Cancer Institute, University College London, London, UK.
⁷ Department of Haematology, UCL Cancer Institute, University College London, London, UK; Developmental Biology and Cancer, UCL Great Ormond Street Institute of Child Health, London, UK.
⁸ Faculty of Biology, University of Wurzburg, Wurzburg, Germany.
⁹ MRC Laboratory for Molecular Cell Biology, University College London, London, UK.
¹⁰ Flow Cytometry Translational Technology Platform, University College London, London, UK.
¹¹ CRUK City of London Centre, UCL Cancer Institute, University College London, London, UK; Department of Cancer Biology, UCL Cancer Institute, University College London, London, UK.
¹² Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA, USA.
¹³ Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
¹⁴ Department of Haematology, UCL Cancer Institute, University College London, London, UK; Developmental Biology and Cancer, UCL Great Ormond Street Institute of Child Health, London, UK; University College London Hospitals NHS Foundation Trust, London, UK. Electronic address: m.mansour@ucl.ac.uk.

PMID: 40378042
DOI: 10.1016/j.celrep.2025.115705

Free article

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

Joana R Costa et al. Cell Rep. 2025.

Free article

. 2025 May 27;44(5):115705.

doi: 10.1016/j.celrep.2025.115705. Epub 2025 May 15.

Authors

Affiliations

¹ Department of Haematology, UCL Cancer Institute, University College London, London, UK.
² Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
³ Department of Haematology, UCL Cancer Institute, University College London, London, UK; Department of Haematology, Great Ormond Street Hospital for Children, London, UK.
⁴ Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
⁵ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁶ Cancer Institute Bioinformatics Hub, UCL Cancer Institute, University College London, London, UK; CRUK City of London Centre, UCL Cancer Institute, University College London, London, UK.
⁷ Department of Haematology, UCL Cancer Institute, University College London, London, UK; Developmental Biology and Cancer, UCL Great Ormond Street Institute of Child Health, London, UK.
⁸ Faculty of Biology, University of Wurzburg, Wurzburg, Germany.
⁹ MRC Laboratory for Molecular Cell Biology, University College London, London, UK.
¹⁰ Flow Cytometry Translational Technology Platform, University College London, London, UK.
¹¹ CRUK City of London Centre, UCL Cancer Institute, University College London, London, UK; Department of Cancer Biology, UCL Cancer Institute, University College London, London, UK.
¹² Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA, USA.
¹³ Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
¹⁴ Department of Haematology, UCL Cancer Institute, University College London, London, UK; Developmental Biology and Cancer, UCL Great Ormond Street Institute of Child Health, London, UK; University College London Hospitals NHS Foundation Trust, London, UK. Electronic address: m.mansour@ucl.ac.uk.

PMID: 40378042
DOI: 10.1016/j.celrep.2025.115705

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.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

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LinkOut - more resources

Full Text Sources

Miscellaneous