Enhancer recruitment of transcription repressors RUNX1 and TLE3 by mis-expressed FOXC1 blocks differentiation in acute myeloid leukemia
Authors
Simeoni, FabrizioRomero-Camarero, Isabel
Camera, Francesco
Amaral, Fabio
Sinclair, Oliver J
Papachristou, E. K.
Spencer, Gary J
Lie-A-Ling, Michael
Lacaud, Georges
Wiseman, Daniel H
Carroll, J. S.
Somervaille, Tim C P
Affiliation
Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4GJIssue Date
2021
Metadata
Show full item recordAbstract
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.Citation
Simeoni F, Romero-Camarero I, Camera F, Amaral FMR, Sinclair OJ, Papachristou EK, et al. Enhancer recruitment of transcription repressors RUNX1 and TLE3 by mis-expressed FOXC1 blocks differentiation in acute myeloid leukemia. Vol. 36, Cell Reports. Elsevier BV; 2021. p. 109725.Journal
Cell ReportsDOI
10.1016/j.celrep.2021.109725PubMed ID
34551306Additional Links
https://dx.doi.org/10.1016/j.celrep.2021.109725Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1016/j.celrep.2021.109725