SOX4 is an upstream transcriptional regulator of FOXC1 in acute myeloid leukemia [ATAC-seq]
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ABSTRACT:
PROVIDER: PRJNA729506 | ENA |
REPOSITORIES: ENA
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Project description:SOX4 is an upstream transcriptional regulator of FOXC1 in acute myeloid leukemia [MeDIP-seq]
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Project description:SOX4 is an upstream transcriptional regulator of FOXC1 in acute myeloid leukemia [RNA-seq]
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Project description:SOX4 is an upstream transcriptional regulator of FOXC1 in acute myeloid leukemia [4C-seq]
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Project description:Transcription factors are key determinants in myeloid identity and differentiation fates and when mis- expressed or mutated, they cause a differentiation block, the cardinal feature of acute myeloid leukaemia (AML). The Forkhead family transcription factor FOXC1, is de-repressed in a lineage- inappropriate manner in approximately 30% of cases of HOXAhigh AML with functional consequences and prognostic significance. The mechanisms by which FOXC1 is mis-expressed remain to be determined and they presumably belong to a network of transcription factors and chromatin proteins that represent attractive therapeutic targets in AML. We performed an integrative omics analysis using AML primary samples and discovered an active distal enhancer at the FOXC1 topologically associated domain (TAD) that is more acetylated, accessible and differentially interacts with FOXC1, positively regulating its expression in FOXC1high AML. Moreover, through integrated next generation sequencing and functional analysis, we identified SOX4 as one of the upstream regulators of FOXC1 in leukaemia, where it is broadly expressed and associated with a high level of differentiation block. SOX4 binds at multiple sites across the FOXC1 TAD and directly controls its expression. Genome wide, SOX4 is preferentially bound at sites of accessible and acetylated chromatin at both promoter regions and active enhancers of transcription factors genes that include FOXC1, where it acts as a transcription activator. Our studies reveal a set of regulatory elements that control FOXC1 expression and highlight the role of SOX4 as a transcriptional activator that promotes differentiation block in AML.
2025-01-21 | GSE225519 | GEO
Project description:Foxc1 has been identified to participate in regulating genes expression directly by binding their promoters as well as playing various roles in signal transduction within the cells. In this study, we found that, in F9 Embryonal Carcinoma cells, Foxc1 repressed the promoter’s transcription activity by binding the region of 1Kb upstream of Transcription Start Site within Nanog promoter.To understand more functions of Foxc1, streptavidin-biotin affinity purification combined with Liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) analysis was carried out.Bioinformatic analysis identified 360 proteins which may act as Foxc1 interactors.
2021-09-09 | PXD022178 | Pride
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.
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Project description:TBX2 a novel upstream regulator of labor
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Project description:Mutation or epigenetic silencing of the transcription factor C/EBP? is observed in ~10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but down-stream targets relevant for leukemogenesis are not known. Here we identify Sox4 as a direct target of C/EBP? whereby its expression is inversely correlated with C/EBP? activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. Gene expression profiles of leukemia initiating cells (LICs) from both Sox4 overexpression and murine mutant C/EBP? AML models clustered together, but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBP? inactivation contributes to the development of leukemias with a distinct LIC phenotype. K/L (bi-allelic Cebpa mutations) leukemic mice and Sox4 overexprssing leukemic mice were used for RNA extraction and hybridization on Affymetrix microarrays. We compared these microarray samples with the C57/BL6 wild type mice.
2013-03-23 | E-GEOD-45430 | biostudies-arrayexpress
Project description:Mutation or epigenetic silencing of the transcription factor C/EBPa is observed in ~10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but down-stream targets relevant for leukemogenesis are not known. Here we identify Sox4 as a direct target of C/EBPa whereby its expression is inversely correlated with C/EBPa activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. Gene expression profiles of leukemia initiating cells (LICs) from both Sox4 overexpression and murine mutant C/EBPa AML models clustered together, but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBPa inactivation contributes to the development of leukemias with a distinct LIC phenotype. A ChIP-seq sample of C/EBPa in Macrophages is used in this study
2014-01-08 | E-GEOD-50565 | biostudies-arrayexpress
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