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Whole transcriptome profiling of macrophage-DC progenitors (MDPs) and common monocyte progenitors (cMoPs) from Dnmt1+/+ and Dnmt1c/chip mice

ABSTRACT: Dendritic cells (DCs) are critical immune regulators involved in autoimmune diseases, but exploiting them clinically requires a detailed picture on the mechanisms orchestrating their development. DNA methylation is attractive in this regard because it is reversible and as such allows therapeutic manipulation. Combining single cell transplantation assays with whole-genome methylation assessment and with mice expressing reduced DNA methyltransferase 1 levels, we show that conventional and plasmacytoid DCs arise from myeloid-restricted hematopoietic stem cells (HSCs), suggesting that both subsets can develop independently of the lymphoid pathway. DC commitment by these HSCs requires an intrinsically high methylation threshold to establish expression of DC genes, particularly the Flt3 cytokine receptor. Reducing methylation depleted DCs and ameliorated systemic lupus erythematosus in mice. These studies shed novel light on the DC origin, show how lineage- and subset-specific methylation dynamics regulate DC fate and provide a potential rationale for targeting DCs in autoimmunity by hypomethylating agents.

ORGANISM(S): Mus musculus

PROVIDER: GSE163295 | GEO | 2021/11/22

REPOSITORIES: GEO

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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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Whole transcriptome profiling of macrophage-DC progenitors (MDPs) and common monocyte progenitors (cMoPs) from Dnmt1+/+ and Dnmt1c/chip mice

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