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Enhancer binding of RUNX1 and Groucho family repressor TLE3 is stabilized by FOXC1 to block differentiation in acute myeloid leukemia [ChIP-Seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE159691 | GEO | 2021/08/13

REPOSITORIES: GEO

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Project description:Disrupting mutations of the RUNX1 gene are found in 10% of patients with myelodysplasia (MDS) and 30% of patients with acute myeloid leukemia (AML). Previous studies have revealed an increase in hematopoietic stem cells (HSCs) and multipotent progenitor (MPP) cells in conditional Runx1-knockout (KO) mice, but the molecular mechanism is unresolved. We investigated the myeloid progenitor (MP) compartment in KO mice, arguing that disruptions at the HSC/MPP level may be amplified in downstream cells. We demonstrate that the MP compartment is increased more than fivefold in Runx1 KO mice, with a prominent skewing toward megakaryocyte (Meg) progenitors. Runx1- deficient granulocyte-macrophage progenitors are characterized by increased cloning capacity, impaired development into mature cells, and HSC and Meg transcription signatures. An HSC/MPP subpopulation expressing Meg markers was also increased in Runx1-deficient mice. Rescue experiments coupled with transcriptome analysis and Runx1 DNA-binding assays demonstrated that commitment is marked by Runx1 suppression of genes encoding adherence and motility proteins (Tek, Jam3, Plxnc1, Pcdh7, and Selp) that support HSCâMeg interactions with the BM niche. In vitro assays confirmed that enforced Tek expression in HSCs/MPPs increases Meg output. Interestingly, besides this key repressor function of Runx1 to control lineage decisions and cell numbers in progenitors, our study also revealed a critical activating function in erythroblast differentiation, in addition to its known importance in Meg and granulocyte/monocyte (G/M) maturation. Thus both repressor and activator functions of Runx1 at multiple hematopoietic stages and lineages likely contribute to the tumor suppressor activity in MDS and AML. GMP were isolated either from Runx1+/+-Tg(vav-Cre) and Runx1fl/fl-Tg(vav-Cre) mice or from mice transplanted with Runx1fl/fl-Tg(vav-Cre) progenitors engineered to express GFP with RUNX1-ERt2 or ERt2. RUNX1-ERt2 activity was induced by i.p. injection of tamoxifen on 3 consecutive days prior to GMP isolation.

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Enhancer binding of RUNX1 and Groucho family repressor TLE3 is stabilized by FOXC1 to block differentiation in acute myeloid leukemia [ChIP-Seq]

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