Missense mutations in transcription factor GATA1 underlie several distinct forms of anemia and thrombocytopenia. Clinical severity depends on the site and type of substitution, and distinct substiutions of the same residue produce disparate phenotypes. To investigate the effect of GATA1 missense mutations on erythroid differentiation we expressed conditionally activated wild type or mutant versions of GATA1 in GATA1-null G1E cells.
Analysis of disease-causing GATA1 mutations in murine gene complementation systems.
Specimen part
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Function of GATA factors in the adult mouse liver.
Specimen part, Treatment
View SamplesG1E cells are a Gata-1 erythroid-committed cell line derived from targeted disruption of Gata-1 in embryonic stem cells. The ER4 subclone contains an inducible form of Gata-1 (Gata-1-ER, Gata-1 fused to the estradiol receptor ligand binding domain). We performed transcriptome analysis using this cell line. Estradiol was added to culture medium triggering synchronous and homogenous differentiation. At various time points, RNA was sampled and analyzed using the Affymetrix MG-U74Av2 platform. Three biological replicas (A,B, and C) were performed. The thirty hour time course corresponds to development from the late BFU-E stage through the orthochromatic erythroblast stage.
Global regulation of erythroid gene expression by transcription factor GATA-1.
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View SamplesAnalysis of changes in gene expression following hepatocyte specific deletion of GATA4 and GATA6 in adult mice. Results showed that the subset of differentially expressed genes had liver specific ontologies.
Function of GATA factors in the adult mouse liver.
Specimen part
View SamplesAnalysis of changes in gene expression following hepatocyte specific deletion of GATA4 in adult mice. Results showed that the subset of differentially expressed genes had liver specific ontologies.
Function of GATA factors in the adult mouse liver.
Specimen part, Treatment
View SamplesThe transcription co-factor FOG1 interacts with the chromatin remodeling complex NuRD to mediate gene activation and gene repression during hematopoiesis. We have generated mice with a targeted mutation in the endogenous Fog1 locus that results in an N-ternimal mutation in FOG1 that disrupts the interaction with NuRD.
Pleiotropic platelet defects in mice with disrupted FOG1-NuRD interaction.
Specimen part
View SamplesThe transcription co-factor FOG1 interacts with the chromatin remodeling complex NuRD to mediate gene activation and gene repression during hematopoiesis. We have generated mice with a targeted mutation in the endogenous Fog1 locus that results in an N-ternimal mutation in FOG1 that disrupts the interaction with NuRD.
FOG1 requires NuRD to promote hematopoiesis and maintain lineage fidelity within the megakaryocytic-erythroid compartment.
Specimen part
View SamplesCombinatorial actions of relatively few transcription factors control hematopoietic differentiation. To investigate this process in erythro-megakaryopoiesis, we correlated the genome-wide chromatin occupancy signatures of four master hematopoietic transcription factors (GATA1, GATA2, TAL1, and FLI1) and three diagnostic histone modification marks with the gene expression changes that occur during development of primary cultured megakaryocytes (MEG) and primary erythroblasts (ERY) from murine fetal liver hematopoietic stem/progenitor cells. We identified a robust, genome-wide mechanism of MEG-specific lineage priming by a previously described stem/progenitor cell-expressed transcription factor heptad (GATA2, LYL1, TAL1, FLI1, ERG, RUNX1, LMO2) binding to MEG-associated cis-regulatory modules (CRMs) in multipotential progenitors. This is followed by genome-wide GATA factor switching that mediates further induction of MEG-specific genes following lineage commitment. Interaction between GATA and ETS factors appears to be a key determinant of these processes. In contrast, ERY-specific lineage priming is biased toward GATA2-independent mechanisms. In addition to its role in MEG lineage priming, GATA2 plays an extensive role in late megakaryopoiesis as a transcriptional repressor at loci defined by a specific DNA signature. Our findings reveal important new insights into how ERY and MEG lineages arise from a common bipotential progenitor via overlapping and divergent functions of shared hematopoietic transcription factors.
Divergent functions of hematopoietic transcription factors in lineage priming and differentiation during erythro-megakaryopoiesis.
Specimen part
View SamplesCombinatorial actions of relatively few transcription factors control hematopoietic differentiation. To investigate this process in erythro-megakaryopoiesis, we correlated the genome-wide chromatin occupancy signatures of four master hematopoietic transcription factors (GATA1, GATA2, SCL/TAL1 and FLI1) and three diagnostic histone modification marks with the gene expression changes that occur during development of primary megakaryocytes (MEG) and erythroblasts (ERY) from murine fetal liver hematopoietic stem/progenitor cells. We identified a robust, genome-wide mechanism of MEG-specific lineage priming by a previously described stem/progenitor cell-expressed transcription factor heptad (GATA2, LYL1, SCL/TAL1, FLI1, ERG, RUNX1, LMO2) binding to MEG-specific cis-regulatory modules in multipotential hematopoietic progenitors. This is followed by genome-wide GATA factor switching that mediates further induction of MEG-specific genes following lineage commitment. Interaction between GATA and ETS factors appears to be a key determinant of these processes. In contrast, ERY-specific lineage priming occurs is biased toward GATA2-independent mechanisms. In addition to its role in MEG lineage priming, GATA2 plays an extensive role in late megakaryopoiesis as a transcriptional repressor at loci defined by a specific DNA signature. Our findings reveal important new insights into how ERY and MEG lineages arise from a common bipotential precursor via overlapping and divergent functions of shared hematopoietic transcription factors.
Divergent functions of hematopoietic transcription factors in lineage priming and differentiation during erythro-megakaryopoiesis.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Functions of BET proteins in erythroid gene expression.
Specimen part, Treatment
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