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

Cell Rep. 2021 Sep 21;36(12):109725. doi: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Cell Differentiation*
  • Cell Line, Tumor
  • Chromatin / metabolism
  • Co-Repressor Proteins / genetics
  • Co-Repressor Proteins / metabolism*
  • Core Binding Factor Alpha 2 Subunit / chemistry
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / metabolism*
  • Enhancer Elements, Genetic
  • Forkhead Transcription Factors / antagonists & inhibitors
  • Forkhead Transcription Factors / deficiency
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Histone Deacetylase 1 / genetics
  • Histone Deacetylase 1 / metabolism
  • Humans
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Monocytes / cytology
  • Monocytes / metabolism
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Domains
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Up-Regulation

Substances

  • CCAAT-Enhancer-Binding Proteins
  • CEBPA protein, human
  • Chromatin
  • Co-Repressor Proteins
  • Core Binding Factor Alpha 2 Subunit
  • FOXC1 protein, human
  • Forkhead Transcription Factors
  • KLF2 protein, human
  • Kruppel-Like Transcription Factors
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • RUNX1 protein, human
  • TLE3 protein, human
  • HDAC1 protein, human
  • Histone Deacetylase 1