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

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

PROVIDER: PRJNA670200 | ENA |

REPOSITORIES: ENA

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

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

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

2021-08-13 | GSE159691 | GEO

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

Project description:Enhancer binding of RUNX1 and Groucho family repressor TLE3 is stabilized by FOXC1 to block differentiation in acute myeloid leukemia

| PRJNA670197 | ENA

Enhancer recruitment of transcription repressors RUNX1 and TLE3 by mis-expressed FOXC1 blocks differentiation in acute myeloid leukemia

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

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

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

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-08-13 | GSE159693 | GEO

The Groucho/Tle coregulators are essential for early thymic progenitors and T-cell lineage specification [RNA-seq]

Project description:The goal of this study is to determine the functional requirements for Groucho/Tle coregulators in early stages of T cell development. By ablating three mammalian homologues, Tle1, Tle3, and Tle4 genes, we found that Tle1/3/4 are essential for repressing non-T cell lineage potential in early thymic progenitors, and therefore pivotal for T-cell lineage specification.

2022-11-06 | GSE217025 | GEO

The Groucho/Tle coregulators are essential for early thymic progenitors and T-cell lineage specification [Cut&Run]

2022-11-06 | GSE217024 | GEO

The Groucho/Tle coregulators are essential for early thymic progenitors and T-cell lineage specification [ATAC-seq]

2022-11-06 | GSE217023 | GEO

Adipose subtype-selective recruitment of TLE3 in thermogenic gene programs

Project description:Transcriptional effectors of white adipocyte-selective gene expression have not been described. TLE3 is a white-selective cofactor that acts reciprocally with the brown-selective cofactor Prdm16 to specify lipid storage and thermogenic gene programs. When expressed at elevated levels in brown fat, TLE3 counters Prdm16, suppressing brown-selective genes and inducing white-selective genes, resulting in impaired fatty acid oxidation and thermogenesis. To further test the functional consequences of the changes in BAT phenotype in aP2-TLE3 Tg mice, we challenged them with cold exposure at 4C. aP2-TLE3 Tg mice had an impaired ability to respond to cold exposure compared to littermate control mice, as evidenced by a marked drop in core body temperature. Transgenic mice expressing TLE3 from the aP2 enhancer and wild type mice were housed individually without food and bedding immediately before the start of experiments. Mice were allowed free access to water and placed at 4C for 5 hours while core body temperature was monitored every hour using a rectal probe. For microarray experiments of BAT, RNA was extracted and pooled from 4 mice in each group.

2013-09-27 | E-GEOD-51223 | biostudies-arrayexpress

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