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

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

Summary: 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 k...

Full description

Saved in:
Bibliographic Details
Main Authors: Joana R. Costa, Yang Li, Nurkaiyisah Zaal Anuar, David O’Connor, Sunniyat Rahman, Tanya Rapoz-D’Silva, Kent T.M. Fung, Rachael Pocock, Zhaodong Li, Stephen Henderson, Lingyi Wang, Mateja E. Krulik, Sara Hyseni, Nivedita Singh, George Morrow, Yanping Guo, Daisy O.F. Gresham, Javier Herrero, Richard G. Jenner, A. Thomas Look, Dennis Kappei, Marc R. Mansour
Format: Article
Language:English
Published: Elsevier 2025-05-01
Series:Cell Reports
Subjects:
CP: Cancer
CP: Molecular biology
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124725004760
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Summary: 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.
ISSN:2211-1247

Similar Items