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Enhancer recruitment of transcription repressors RUNX1 and TLE3 by mis-expressed FOXC1 blocks differentiation in acute myeloid leukemia.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Simeoni, Fabrizio 
Romero-Camarero, Isabel 
Camera, Francesco 
Amaral, Fabio MR 
Sinclair, Oliver J 

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.

Description

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

Journal Title

Cell Rep

Conference Name

Journal ISSN

2211-1247
2211-1247

Volume Title

36

Publisher

Elsevier BV
Sponsorship
Cancer Research UK (C14303/A17197)
Cancer Research UK (C9545/A29580_do not transfer)
Cancer Research UK (CB4220)