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| Status |
Public on Aug 13, 2021 |
| Title |
Enhancer binding of RUNX1 and Groucho family repressor TLE3 is stabilized by FOXC1 to block differentiation in acute myeloid leukemia [ChIP-Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
A differentiation block is the cardinal pathologic feature of acute myeloid leukaemia (AML) but the underlying mechanisms are incompletely understood. Despite absent expression in normal hematopoietic lineages, the Forkhead family transcription factor FOXC1, which is a critical regulator of normal mesenchymal and mesodermal differentiation, is highly expressed in ~20% of cases of AML where it confers a block to monocyte/macrophage lineage differentiation. Through integrated proteomics and bioinformatics approaches, we discovered that FOXC1 interacts with RUNX1 through its Forkhead DNA binding domain and that the two factors co-occupy a discrete set of primed or active enhancers distributed close to monocyte/macrophage differentiation genes. FOXC1 stabilises association of RUNX1, HDAC1 and the Groucho family repressor protein TLE3 at these sites. FOXC1 knockdown induced loss of these repressor proteins and gain of CEBPA binding, with localised increase in enhancer acetylation; nearby genes, including KLF2, were up regulated. A genome-wide redistribution of RUNX1 and TLE3 binding from enhancers to promoters was triggered by FOXC1 knockdown leading to repression of self-renewal genes including MYC and MYB. Thus, FOXC1 misexpression confers a differentiation block in AML by stabilising recruitment of a RUNX1/HDAC1/TLE3 repressor complex at primed or active enhancers close to genes which control monocyte/macrophage lineage differentiation.
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| Overall design |
Human Fujioka AML cells were infected with a lentivirus targeting FOXC1 for KD or a non-targeting control (NTC). Primary human AML cells were obtained from the Manchester Cancer Research Centre Tissue Biobank (approved by the South Manchester Research Ethics Committee). The Biobank archive was searched for samples from patients with high expression of FOXC1 and sufficient viable cells from ChIP sequencing.
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| Contributor(s) |
Somervaille TC |
| Citation(s) |
34551306 |
| |
| Submission date |
Oct 20, 2020 |
| Last update date |
Oct 13, 2021 |
| Contact name |
Tim C Somervaille |
| E-mail(s) |
[email protected]
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| Organization name |
Cancer Research UK
|
| Department |
Manchester Institute
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| Lab |
Leukaemia Biology
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| Street address |
Wilmslow Rd
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| City |
Manchester |
| ZIP/Postal code |
M20 4BX |
| Country |
United Kingdom |
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| Platforms (2) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (26)
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| This SubSeries is part of SuperSeries: |
| GSE159693 |
Enhancer binding of RUNX1 and Groucho family repressor TLE3 is stabilized by FOXC1 to block differentiation in acute myeloid leukemia |
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| Relations |
| BioProject |
PRJNA670201 |
| SRA |
SRP287839 |
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