Enhancer binding of RUNX1 and Groucho family repressor TLE3 is stabilized by FOXC1 to block differentiation in acute myeloid leukemia
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE159693 | GEO | 2021/08/13
REPOSITORIES: GEO
Similar Datasets
Project description: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.
2021-08-13 | GSE159690 | GEO
Project description: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.
2021-08-13 | GSE159691 | GEO
Project description:Enhancer binding of RUNX1 and Groucho family repressor TLE3 is stabilized by FOXC1 to block differentiation in acute myeloid leukemia
| PRJNA670197 | ENA
Project description: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.
| S-EPMC8480281 | biostudies-literature
Project description:Enhancer binding of RUNX1 and Groucho family repressor TLE3 is stabilized by FOXC1 to block differentiation in acute myeloid leukemia [RNA-Seq]
| PRJNA670200 | ENA
Project description:Enhancer binding of RUNX1 and Groucho family repressor TLE3 is stabilized by FOXC1 to block differentiation in acute myeloid leukemia [ChIP-Seq]
| PRJNA670201 | ENA
Project description:Despite absent expression in normal hematopoiesis, the Forkhead factor FOXC1, a critical mesenchymal differentiation regulator, is highly expressed in ~30% of HOXAhigh AML to confer blocked monocyte/macrophage differentiation. Through integrated proteomics and bioinformatics, we discovered that FOXC1 and RUNX1 interact through Forkhead and Runt domains respectively and cooccupy primed and active enhancers distributed close to differentiation genes. FOXC1 stabilises association of RUNX1, HDAC1 and Groucho repressor TLE3 to limit enhancer activity: FOXC1 knockdown induced loss of repressor proteins, gain of CEBPA binding, enhancer acetylation and upregulation of nearby genes, including KLF2. Furthermore, it triggered 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 stabilising enhancer binding of a RUNX1/HDAC1/TLE3 transcription repressor complex, to oncogenic effect.
2021-08-08 | PXD027740 | Pride
Project description:Defining the role of epigenetic regulators in hematopoiesis has become critically important, because recurrent mutations or aberrant expression of these genes has been identified in both myeloid and lymphoid hematological malignancies. We found that PRMT4, a type I arginine methyltransferase whose function in normal and malignant hematopoiesis is unknown, is overexpressed in acute myelogenous leukemia patient samples. Overexpression of PRMT4 blocks the myeloid differentiation of human stem/progenitor cells (HSPCs), whereas its knockdown is sufficient to induce myeloid differentiation of HSPCs. We demonstrated that PRMT4 represses the expression of miR-223 in HSPCs via the methylation of RUNX1, which triggers the assembly of a multiprotein repressor complex that includes DPF2. As part of the feedback loop, PRMT4 expression is repressed posttranscriptionally by miR-223. Depletion of PRMT4 results in differentiation of myeloid leukemia cells in vitro and their decreased proliferation in vivo. Thus, targeting PRMT4 holds potential as a novel therapy for acute myelogenous leukemia.
| S-EPMC4073674 | biostudies-literature
Project description:The E2A-HLF fusion gene, formed by the t(17;19)(q22;p13) chromosomal translocation in leukemic pro-B cells, encodes a chimeric transcription factor consisting of the transactivation domain of E2A linked to the bZIP DNA-binding and protein dimerization domain of hepatic leukemia factor (HLF). This oncoprotein blocks apoptosis induced by growth factor deprivation or irradiation, but the mechanism for this effect remains unclear. We therefore performed representational difference analysis (RDA) to identify downstream genetic targets of E2A-HLF, using a murine FL5.12 pro-B cell line that had been stably transfected with E2A-HLF cDNA under the control of a zinc-regulated metallothionein promoter. Two RDA clones, designated RDA1 and RDA3, were differentially upregulated in E2A-HLF-positive cells after zinc induction. The corresponding cDNAs encoded two WD40 repeat-containing proteins, Grg2 and Grg6. Both are related to the Drosophila protein Groucho, a transcriptional corepressor that lacks DNA-binding activity on its own but can act in concert with other proteins to regulate embryologic development of the fly. Expression of both Grg2 and Grg6 was upregulated 10- to 50-fold by E2A-HLF. Immunoblot analysis detected increased amounts of two additional Groucho-related proteins, Grg1 and Grg4, in cells expressing E2A-HLF. A mutant E2A-HLF protein with a disabled DNA-binding region also mediated pro-B cell survival and activated Groucho-related genes. Among the transcription factors known to interact with Groucho-related protein, only RUNX1 was appreciably downregulated by E2A-HLF. Our results identify a highly conserved family of transcriptional corepressors that are activated by E2A-HLF, and they suggest that downregulation of RUNX1 may contribute to E2A-HLF-mediated leukemogenesis.
| S-EPMC87312 | biostudies-literature
Project description:The T-box family of transcription factors, defined by a conserved DNA binding domain called the T-box, regulate various aspects of embryogenesis by activating and/or repressing downstream genes. In spite of the biological significance of the T-box proteins, how they regulate transcription remains to be elucidated. Here we show that the Groucho/TLE-associated protein Ripply converts T-box proteins from activators to repressors. In cultured cells, zebrafish Ripply1, an essential component in somite segmentation, and its structural relatives, Ripply2 and -3, suppress the transcriptional activation mediated by the T-box protein Tbx24, which is coexpressed with ripply1 during segmentation. Ripply1 associates with Tbx24 and converts it to a repressor. Ripply1 also antagonizes the transcriptional activation of another T-box protein, No tail (Ntl), the zebrafish ortholog of Brachyury. Furthermore, injection of a high dosage of ripply1 mRNA into zebrafish eggs causes defective development of the posterior trunk, similar to the phenotype observed in homozygous mutants of ntl. A mutant form of Ripply1 defective in association with Tbx24 also lacks activity in zebrafish embryos. These results indicate that the intrinsic transcriptional property of T-box proteins is controlled by Ripply family proteins, which act as specific adaptors that recruit the global corepressor Groucho/TLE to T-box proteins.
| S-EPMC2423164 | biostudies-literature