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Identification and Characterization of Hoxa9 Binding Sites in Hematopoietic Cells

ABSTRACT: The clustered homeobox proteins play crucial roles in development, hematopoiesis and leukemia yet the targets they regulate and their mechanisms of action are poorly understood. Here, we identified the binding sites for Hoxa9 and the Hox cofactor Meis1 on a genome-wide level and profiled their associated epigenetic modifications and transcriptional targets. Hoxa9 and the Hox cofactor Meis1 co-bind at hundreds of highly evolutionarily-conserved sites, most of which are distant from transcription start sites. These sites show high levels of histone H3K4 monomethylation and CBP/P300 binding characteristic of enhancers. Furthermore, a subset of these sites shows enhancer activity in transient transfection assays. Many Hoxa9 and Meis1 binding sites are also bound by PU.1 and other lineage-restricted transcription factors previously implicated in establishment of myeloid enhancers. Conditional Hoxa9 activation is associated with CBP/P300 recruitment, histone acetylation and transcriptional activation of a network of proto-oncogenes including Erg, Flt3, Lmo2, Myb and Sox4. Collectively this work suggests that Hoxa9 regulates transcription by interacting with enhancers of genes important for hematopoiesis and leukemia.

ORGANISM(S): Mus musculus

PROVIDER: GSE33509 | GEO | 2011/12/04

SECONDARY ACCESSION(S): PRJNA154277

REPOSITORIES: GEO

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Identification and Characterization of Hoxa9 Binding Sites in Hematopoietic Cells

Project description:The clustered homeobox proteins play crucial roles in development, hematopoiesis and leukemia yet the targets they regulate and their mechanisms of action are poorly understood. Here, we identified the binding sites for Hoxa9 and the Hox cofactor Meis1 on a genome-wide level and profiled their associated epigenetic modifications and transcriptional targets. Hoxa9 and the Hox cofactor Meis1 co-bind at hundreds of highly evolutionarily-conserved sites, most of which are distant from transcription start sites. These sites show high levels of histone H3K4 monomethylation and CBP/P300 binding characteristic of enhancers. Furthermore, a subset of these sites shows enhancer activity in transient transfection assays. Many Hoxa9 and Meis1 binding sites are also bound by PU.1 and other lineage-restricted transcription factors previously implicated in establishment of myeloid enhancers. Conditional Hoxa9 activation is associated with CBP/P300 recruitment, histone acetylation and transcriptional activation of a network of proto-oncogenes including Erg, Flt3, Lmo2, Myb and Sox4. Collectively this work suggests that Hoxa9 regulates transcription by interacting with enhancers of genes important for hematopoiesis and leukemia. To identify the genome-wide binding sites for Hoxa9 and the Hox cofactor Meis1

2011-12-04 | E-GEOD-33509 | biostudies-arrayexpress

Epigenetic profiling of histone H3K4me1, H3K4me3, H3K27me3, H3ac, H4ac, CBP and P300 using ChIP-chip

Project description:The clustered homeobox proteins play crucial roles in development, hematopoiesis and leukemia yet the targets they regulate and their mechanisms of action are poorly understood. Here, we identified the binding sites for Hoxa9 and the Hox cofactor Meis1 on a genome-wide level and profiled their associated epigenetic modifications and transcriptional targets. Hoxa9 and the Hox cofactor Meis1 co-bind at hundreds of highly evolutionarily-conserved sites, most of which are distant from transcription start sites. These sites show high levels of histone H3K4 monomethylation and CBP/P300 binding characteristic of enhancers. Furthermore, a subset of these sites shows enhancer activity in transient transfection assays. Many Hoxa9 and Meis1 binding sites are also bound by PU.1 and other lineage-restricted transcription factors previously implicated in establishment of myeloid enhancers. Conditional Hoxa9 activation is associated with CBP/P300 recruitment, histone acetylation and transcriptional activation of a network of proto-oncogenes including Erg, Flt3, Lmo2, Myb and Sox4. Collectively this work suggests that Hoxa9 regulates transcription by interacting with enhancers of genes important for hematopoiesis and leukemia. Enriched Hoxa9 and Meis1 regions and a selected set of the nearest 360 TSSs were tiled onto Nimblegen custom arrays (Mus musculus 8, Feb 2006) with 50-mer probes (average spacing of 35bp), along with 60 negative control sequences that were selected randomly from the mouse genome

2011-11-09 | E-GEOD-33517 | biostudies-arrayexpress

Epigenetic profiling of histone H3K4me1, H3K4me3, H3K27me3, H3ac, H4ac, CBP and P300 using ChIP-chip

2011-11-09 | GSE33517 | GEO

The role of Hoxa9 and Meis1 in development of acute myeloid leukemia

2017-04-27 | GSE74566 | GEO

The role of Hoxa9 and Meis1 in development of acute myeloid leukemia (mRNA)

2016-09-01 | GSE75272 | GEO

The role of Hoxa9 and Meis1 in development of acute myeloid leukemia (mRNA)

Project description:OBJECTIVE: MEIS1, a HOX cofactor, collaborates with multiple HOX proteins, such as HOXA9, to accelerate the onset of acute myeloid leukemia (AML) through largely unknown molecular mechanisms. To further resolve these mechanisms, we conducted a structure-function analysis of Meis1 and gene expression profiling, in the context of Hoxa9 leukemogenesis. RESULTS: We show, in a murine bone marrow transplantation model, that the homeodomain of Meis1 is required for leukemogenic collaboration with Hoxa9. Gene expression profiling of a Hoxa9 preleukemic cell line transduced with wild-type or Meis1 homeodomain mutant reveal deregulation of multiple genes including a set not previously implicated as Meis1 targets. Murine bone marrow cells transduced with Hoxa9-GFP + empty MIY vector were compared to Hoxa9+Meis1 cells or Hoxa9+Meis1 with deleted homeodomain (DHD) cells and cultured for three or four weeks before harvest for miRNA expression array. Four independent experiments were performed for each of the three different conditions included in the study. Cells from all samples were also transplanted into lethally irradiated mice to test for their transforming and leukemic potential.

2016-09-01 | E-GEOD-75272 | biostudies-arrayexpress

Hoxa9 and Meis1 cooperatively induce addiction to Syk signaling by suppressing miR-146a in acute myeloid leukemia

Project description:The transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression but is currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive (phospho)proteomic analysis revealed that Meis1 increased Syk protein expression and activity. Syk upregulation occurs through a Meis1-dependent feed-forward loop. By dissecting this loop, we show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU.1. In the context of Hoxa9 overexpression, Syk induces Meis1, recapitulating several leukemogenic features of Hoxa9/Meis1-driven leukemia. Finally, we show that Syk inhibition disrupts the identified regulatory loop, prolonging survival of mice with Hoxa9/Meis1-driven leukemia.

2017-06-14 | PXD004192 | Pride

Identification and characterization of Hoxa9 binding sites in hematopoietic cells

Project description:This SuperSeries is composed of the following subset Series: GSE21299: Expression data from murine cell line transduced with epitope tagged forms of Hoxa9 GSE33509: Identification and Characterization of Hoxa9 Binding Sites in Hematopoietic Cells GSE33517: Epigenetic profiling of histone H3K4me1, H3K4me3, H3K27me3, H3ac, H4ac, CBP and P300 using ChIP-chip Refer to individual Series

2011-12-05 | E-GEOD-33518 | biostudies-arrayexpress

Gene expression profiling of Hox-driven AML overexpressing JMJD1C

Project description:JMJD1C, a Jumonji C (JmjC) domain-containing histone demethylase, has been reported as a direct cofactor of oncogenic transcription factor HOXA9. To identify JMJD1C downstream effectors, we performed a genome-wide gene expression profiling experiment. Our microarray analysis identified a new role for JMJD1C in regulating a cancer metabolic program in HOX-driven AML. GFP+ HOXA9/MEIS1-mediated pre-leukemic stem cells were transduced with retroviruses carrying JMJD1C or empty vector for the microarray experiment. Each group has 4 samples.

2018-12-30 | E-MTAB-5760 | biostudies-arrayexpress

Genome-wide maps of Meis1, Hoxa9 and Pbx binding sites in murine myeloid leukemia cells

Project description:We have searched genome-wide binding sites of homeodomain proteins important for leukemogenesis in Hoxa9- and Meis1- induced myeloid leukemia cells. Thousands of binding sites of these three family proteins have been identified and many of them are co-localized with those of each others. Hoxa9 and Pbx binding sites were compared between the presence and absence of Meis1 by its knockout in the same cells. In combination of the results with gene expression profiles of the same cells, important downstream target genes of Meis1 in leukemogenesis have been identified.

2016-03-05 | GSE48679 | GEO

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