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The oncofusion protein FUS-ERG targets key hematopoietic regulators and modulates the all-trans retinoic acid signaling pathway in t(16;21) acute myeloid leukemia

ABSTRACT: Fusion proteins involving the ETS factor ERG have been associated with multiple cancers such as Ewing's sarcoma and prostate cancer. In acute myeloid leukemias harboring t(16;21) another ERG fusion protein is expressed, FUS-ERG. Here, we found that this FUS-ERG oncofusion protein acts in the context of a heptad of proteins (ERG, FLI1, GATA2, LYL1, LNMO2, RUNX1 and TAL1) central to proper expression of genes involved in maintaining a stem cell hematopoietic phenotype. Moreover, in t(16;21) FUS-ERG co-occupies genomic regions bound by the nuclear receptor heterodimer RXR-RARA inhibiting target gene expression and interfering with hematopoietic differentiation. All-Trans Retinoic Acid treatment of t(16;21) cells as well as FUS-ERG knock down alleviate the myeloid differentiation block. Together, the results suggest that FUS-ERG acts as a transcriptional repressor of the retinoic acid signaling pathway.

ORGANISM(S): Homo sapiens

PROVIDER: GSE60477 | GEO | 2015/06/23

SECONDARY ACCESSION(S): PRJNA258377

REPOSITORIES: GEO

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The oncofusion protein FUS-ERG targets key hematopoietic regulators and modulates the all-trans retinoic acid signaling pathway in t(16;21) acute myeloid leukemia

Project description:Fusion proteins involving the ETS factor ERG have been associated with multiple cancers such as Ewing's sarcoma and prostate cancer. In acute myeloid leukemias harboring t(16;21) another ERG fusion protein is expressed, FUS-ERG. Here, we found that this FUS-ERG oncofusion protein acts in the context of a heptad of proteins (ERG, FLI1, GATA2, LYL1, LNMO2, RUNX1 and TAL1) central to proper expression of genes involved in maintaining a stem cell hematopoietic phenotype. Moreover, in t(16;21) FUS-ERG co-occupies genomic regions bound by the nuclear receptor heterodimer RXR-RARA inhibiting target gene expression and interfering with hematopoietic differentiation. All-Trans Retinoic Acid treatment of t(16;21) cells as well as FUS-ERG knock down alleviate the myeloid differentiation block. Together, the results suggest that FUS-ERG acts as a transcriptional repressor of the retinoic acid signaling pathway. Cell lines were used for RNA extraction for RNA-seq and ChIP experiments for ChIP-seq.

2015-06-23 | E-GEOD-60477 | biostudies-arrayexpress

Oncofusion protein AML1-ETO targets ERG factor binding sites in AML

Project description:ERG has been identified as an essential factor for the function and maintenance of adult hematopoietic stem cells and high ERG expression is a negative prognostic marker for treatment outcome in AML. The molecular function of ERG and its interplay with other factors is however largely unknown. Here we demonstrate that ERG has cell type specific distributions in normal CD34+ myeloid progenitors and in AML cells and identify ERG as a potential pioneering protein for binding of oncofusion protein complexes. In addition, we identify H3 acetylation as the epigenetic mark preferentially associated with ERG binding. This intimate connection between ERG binding and H3 acetylation implies that one of the molecular strategies of the oncofusion proteins PML-RARa and AML1-ETO could involve the targeting of histone deacetylase activities to ETS factor bound hematopoietic regulatory sites. Examination of AML1-ETO, RUNX1, CBFb, HEB, FLI1 and ERG binding sites (ChIP-seq) in leukemic and normal hematopoietic cells, association with chromatin modifications and expression (RNA-seq) analysis of an AML1-ETO expressing cell line (SKNO-1)

2012-09-18 | E-GEOD-23730 | biostudies-arrayexpress

Oncofusion protein AML1-ETO targets ERG factor binding sites in AML

2012-09-18 | GSE23730 | GEO

Homo sapiens

Project description:The oncofusion protein FUS-ERG targets key hematopoietic regulators and modulates the all-trans retinoic acid signaling pathway in t(16;21) acute myeloid leukemia

| PRJNA258377 | ENA

AML associated oncofusion proteins PML-RARA, AML1-ETO and CBFB-MYH11 target RUNX/ETS-factor binding sites to modulate H3ac levels and drive leukemogenesis

Project description:Chromosomal translocations are one of the hallmarks of acute myeloid leukemia (AML), often leading to gene fusions and expression of an oncofusion protein. Over recent years it has become clear that most of the AML associated oncofusion proteins molecularly adopt distinct mechanisms for inducing leukemogenesis. Still these unique molecular properties of the chimeric proteins converge and give rise to a common pathogenic molecular mechanism. In the present study we compared genome-wide DNA binding and transcriptome data associated with AML1-ETO, CBFB-MYH11 and PML-RARA oncofusion protein expression (GSE46044, GSE23730, GSE30254 and GSE18886) to identify unique and common features. Our analyses revealed targeting of oncofusion binding sites to RUNX1 and ETS-factor occupied genomic regions. In addition, it revealed highly similar expression of common target genes and specific enrichment of several biological pathways critical for maintenance of AML, suggesting oncofusion proteins deregulate common gene programs despite their distinct binding signatures and mechanisms of action.

2016-11-22 | GSE81992 | GEO

Genome-wide Transcription Factor binding maps reveal cell-specific changes in the regulatory architecture of human HSPC [ChIPmentation]

Project description:Hematopoietic stem and progenitor cells (HSPCs) rely on a complex interplay of transcription factors (TFs) to regulate their differentiation into mature blood cells. A heptad of TFs - FLI1, ERG, GATA2, RUNX1, TAL1, LYL1, LMO2 - has been shown to bind to regulatory elements in bulk CD34+ HSPCs. However, whether specific combinations of these TFs have distinct roles in regulating hematopoietic differentiation remained unknown. In this study, we mapped the genome-wide binding profiles of these TFs and other chromatin-associated markers in distinct HSPC subsets (HSC, CMP, GMP, MEP). We found that the heptad occupancy and enhancer-promoter interactions varied significantly across cell types and were associated with cell-type specific gene expression. Moreover, we observed distinct regulatory elements that were enriched with specific combinations of TFs, such as stem-cell specific elements with ERG, and myeloid and megakaryocyte-erythroid specific elements with combinations of FLI1, RUNX1, GATA2, TAL1, LYL1, and LMO2. These findings suggest that specific combinations of TFs play critical roles in the regulation of hematopoietic differentiation, and provide a valuable resource for the development of targeted therapies to manipulate specific HSPC subsets.

2023-08-21 | GSE231422 | GEO

Genome-wide Transcription Factor binding maps reveal cell-specific changes in the regulatory architecture of human HSPC [HiC]

2023-08-21 | GSE231485 | GEO

Genome-wide Transcription Factor binding maps reveal cell-specific changes in the regulatory architecture of human HSPC [HiChIP]

2023-08-21 | GSE231426 | GEO

Genome-wide Transcription Factor binding maps reveal cell-specific changes in the regulatory architecture of human HSPC [ChIP-seq]

2023-08-21 | GSE231425 | GEO

Genome-wide Analysis of Transcriptional Regulators in Human Blood Stem/Progenitor Cells reveals a densely interconnected network of coding and non-coding genes.

Project description:Combinatorial transcription factor (TF) interactions regulate hematopoietic stem cell formation, maintenance and differentiation, and are increasingly recognised as drivers of stem cell signatures in cancer. However, genome-wide combinatorial binding patterns for key regulators do not exist in primary human hematopoietic stem/progenitor cells (HSPCs) and have constrained analysis of the global architecture of the molecular circuits controlling these cells. Here we provide new high-resolution genome-wide binding maps of seven key TFs (FLI1, ERG, GATA2, RUNX1, SCL, LYL1 and LMO2) in human CD34+ HSPCs together with quantitative RNA and microRNA expression profiles. We catalogue binding of TFs at coding genes and microRNA promoters and report that combinatorial binding of all seven TFs is favoured and is associated with differential expression of genes and microRNA in HSPCs. We also uncover a hitherto unrecognized association between FLI1 and RUNX1 pairing in HSPCs, establish a correlation between the density of histone modifications, which mark active enhancers and the number of overlapping TFs at a peak and identify complex relationships between specific miRNAs and coding genes regulated by the heptad. Taken together, this study demonstrates that a heptad of TFs forms a dense auto-regulatory core in human HSPCs with binding of all seven TFs at tissue specific regulatory elements of heptad genes and collectively regulates miRNAs that in turn target components of the heptad and genes regulated by the heptad. Examination of cominatorial binding by 7 transcription factors, 1 IgG control along with mRNA and small RNA sequencing in human CD34+ cells

2013-09-03 | E-GEOD-45144 | biostudies-arrayexpress

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