Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression changes in embryonic PECAM-1+ cells from Gata2 +9.5 enhancer targeted mice

ABSTRACT: We have generated a nonconditionall deletion of an E-box - GATA motif composite element from a putative enhancer 9.5 kb downstream of the Gata2 1S promoter. The mutation results in lethality at E13.5 to E14.5 with embryos exhibiting dectects in definitive hematopoiesis and vasculature integrity. Hematopoietic stem and progenitor cells are nearly absent from these mice and Gata2 expression is severely reduced in Pecam-1+ endothelial cells from E12.5-12.5 embryos but is expressed at normal levels in the embryonic brain. We have employed gene expression profiling in Pecam-1+ cells from wild type and Gata 2+9.5 mutant littermates to identify genes involved in maintaining vascular integrity. The Gata2+9.5 mutation was backcrossed into the C57Bl/6J background. Anti-CD31 antibody bound to magnetic beads was used to enrich for PECAM-1+ cells from four Gata2+9.5 E12.5 embryos and four wild type littermates from two litters. A single RNA sample from each embryo was used for array hybridization.

ORGANISM(S): Mus musculus

SUBMITTER: Kirby Johnson

PROVIDER: E-GEOD-39300 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Transcriptional profiling of mouse comparing in vitro-derived DC progenitors from control and Gata2 conditional knockout mice. Two-condition experiment, Control DCs vs. G2 Knockout DCs. Biological replicates: 4 control, 3 Gata2 knockout, independently grown and harvested. One replicate per array. Dendritic cells (DCs) are critical immune response regulators; however, the mechanism of DC differentiation is not fully understood. Heterozygous germline GATA2 mutations induce GATA2 deficiency syndrome, characterized by monocytopenia, a predisposition to myelodysplasia/acute myeloid leukemia, and a profoundly reduced DC population, which is associated with increased susceptibility to viral infections, impaired phagocytosis, and decreased cytokine production. To define the role of GATA2 in DC differentiation and function, we studied Gata2 conditional knockout and haploinsufficient mice. Gata2 conditional deficiency significantly reduced the DC count, whereas Gata2 haploinsufficiency did not affect this population. GATA2 was required for the in vitro generation of DCs from Linâ??Sca-1+Kit+ cells, common myeloid-restricted progenitors, and common dendritic cell precursors, but not common lymphoid-restricted progenitors or granulocyte-macrophage progenitors, suggesting that GATA2 functions in the myeloid pathway of DC differentiation. Moreover, expression profiling demonstrated reduced expression of myeloid-related genes, including mafb, and increased expression of T-lymphocyte-related genes, including Gata3 and Tcf7, in Gata2-deficient DC progenitors. In addition, GATA2 was found to bind an enhancer element 190-kb downstream region of Gata3, and a reporter assay exhibited significantly reduced luciferase activity after adding this enhancer region to the Gata3 promoter, which was recovered by GATA sequence deletion within Gata3 +190. These results suggest that GATA2 plays an important role in cell fate specification toward the myeloid versus T lymphocyte lineage by regulating lineage-specific transcription factors in DC progenitors, thereby contributing to DC differentiation.

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Gene expression changes in embryonic PECAM-1+ cells from Gata2 +9.5 enhancer targeted mice

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