Enhancer recruitment of transcription repressors RUNX1 and TLE3 by mis-expressed FOXC1 blocks differentiation in acute myeloid leukemia.
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Authors
Simeoni, Fabrizio
Romero-Camarero, Isabel
Camera, Francesco
Amaral, Fabio MR
Sinclair, Oliver J
Papachristou, Evangelia K
Spencer, Gary J
Lie-A-Ling, Michael
Lacaud, Georges
Wiseman, Daniel H
Carroll, Jason S
Somervaille, Tim CP
Publication Date
2021-09-21Journal Title
Cell Rep
ISSN
2211-1247
Publisher
Elsevier BV
Volume
36
Issue
12
Number
ARTN 109725
Pages
109725
Type
Article
This Version
VoR
Physical Medium
Print
Metadata
Show full item recordCitation
Simeoni, F., Romero-Camarero, I., Camera, F., Amaral, F. M., Sinclair, O. J., Papachristou, E. K., Spencer, G. J., et al. (2021). Enhancer recruitment of transcription repressors RUNX1 and TLE3 by mis-expressed FOXC1 blocks differentiation in acute myeloid leukemia.. Cell Rep, 36 (12. ARTN 109725), 109725. https://doi.org/10.1016/j.celrep.2021.109725
Abstract
Despite absent expression in normal hematopoiesis, the Forkhead factor FOXC1, a critical mesenchymal differentiation regulator, is highly expressed in ∼30% of HOXAhigh acute myeloid leukemia (AML) cases to confer blocked monocyte/macrophage differentiation. Through integrated proteomics and bioinformatics, we find that FOXC1 and RUNX1 interact through Forkhead and Runt domains, respectively, and co-occupy primed and active enhancers distributed close to differentiation genes. FOXC1 stabilizes association of RUNX1, HDAC1, and Groucho repressor TLE3 to limit enhancer activity: FOXC1 knockdown induces loss of repressor proteins, gain of CEBPA binding, enhancer acetylation, and upregulation of nearby genes, including KLF2. Furthermore, it triggers genome-wide redistribution of RUNX1, TLE3, and HDAC1 from enhancers to promoters, leading to repression of self-renewal genes, including MYC and MYB. Our studies highlight RUNX1 and CEBPA transcription factor swapping as a feature of leukemia cell differentiation and reveal that FOXC1 prevents this by stabilizing enhancer binding of a RUNX1/HDAC1/TLE3 transcription repressor complex to oncogenic effect.
Keywords
FOXC1, Groucho, RUNX1, TLE3, acute myeloid leukemia, CCAAT-Enhancer-Binding Proteins, Cell Differentiation, Cell Line, Tumor, Chromatin, Co-Repressor Proteins, Core Binding Factor Alpha 2 Subunit, Enhancer Elements, Genetic, Forkhead Transcription Factors, Histone Deacetylase 1, Humans, Kruppel-Like Transcription Factors, Leukemia, Myeloid, Acute, Monocytes, Promoter Regions, Genetic, Protein Binding, Protein Domains, Proto-Oncogene Proteins c-myc, RNA Interference, RNA, Small Interfering, Up-Regulation
Sponsorship
Cancer Research UK (C14303/A17197)
Cancer Research UK (C9545/A29580_do not transfer)
Cancer Research UK (CB4220)
Identifiers
External DOI: https://doi.org/10.1016/j.celrep.2021.109725
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334614
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