GATA2 regulates dendritic cell differentiation

Abstract

Key Points• Conditional Gata2-deficient mice have profoundly reduced DC populations.• Gata2 deficiency in DC progenitors reduced the expression of myeloid-related genes and increased that of T-lymphocyte-related genes.Dendritic cells (DCs) are critical immune response regulators; however, the mechanism of DC differentiation is not fully understood. Heterozygous germ line 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 Lin 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 1190. These results suggest that GATA2 plays an important role in cell-fate specification toward the myeloid vs T-lymphocyte lineage by regulating lineage-specific transcription factors in DC progenitors, thereby contributing to DC differentiation. (Blood. 2016;128(4):508-518)

Establishment of a Screening System to Identify Novel GATA-2 Transcriptional Regulators

“…For example, genome-wide analysis of GATA-2 chromatin occupancy based on the coupling of next-generation DNA-sequencing technology with ChIP-seq demonstrates that a significant GATA-2 peak is not detected in the CD205 locus (Fujiwara et al 2009), presumably excluding the possibility of direct transcriptional regulation of the CD205 gene by GATA-2. We have recently demonstrated that GATA-2 has 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 (Onodera et al 2016). In support of our observations, a previous study suggested that moderate GATA-2 overexpression might induce myeloid expansion after the granulocyte monocyte progenitor stage, while blocking lymphoid differentiation (Nandakumar et al 2015).…”

“…GATA-2 plays an important role in the differentiation of DCs (Onodera et al 2016). Therefore, we evaluated the phenotypic changes by the restoration of GATA-2 expression in DC precursors.…”

GATA Transcription Factors: Basic Principles and Related Human Disorders

“…On the other hand, Emberger syndrome is characterized by primary lymphedema and predisposition to AML (Ostergaard et al 2011). Given that DCs play crucial roles in the immune system and as their numbers are profoundly decreased in GATA2 deficiency syndrome, we recently examined the roles of GATA2 in DC differentiation (Onodera et al 2016). We found greatly reduced numbers of splenic DCs in conditional Gata2 knockout mice.…”

GATA1-Deficient Dendritic Cells Display Impaired CCL21-Dependent Migration toward Lymph Nodes Due to Reduced Levels of Polysialic Acid

“…Patients carrying mutations in the GATA2 gene present with MonoMac disease (an autosomal dominant immunodeficiency caused by the lack of monocytes, DCs, B cells, and NK cells) and are prone to development of myelodysplasia and/or leukemia (32). In addition, conditional GATA2 loss in mice results in severely reduced DC numbers (33).…”