期刊
CELL REPORTS
卷 36, 期 12, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2021.109725
关键词
-
类别
资金
- Cancer Research UK [C5759/A20971, A27412, A20411]
- Kay Kendall Leukaemia Fund Junior Research Fellowship [KKL1185]
- Blood Cancer UK clinician scientist award
- Oglesby Charitable Trust
- Christie Charity
- University of Cambridge
- Hutchison Whampoa Ltd.
- Cancer Research UK
- Manchester-Melbourne GOLDEN PhD studentship
FOXC1 is highly expressed in HOXA(high) AML cases, stabilizing enhancer binding of a RUNX1/HDAC1/TLE3 transcription repressor complex to prevent leukemia cell differentiation.
Despite absent expression in normal hematopoiesis, the Forkhead factor FOXC1, a critical mesenchymal differentiation regulator, is highly expressed in similar to 30% of HOXA(high) 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据