Differential context-dependent effects of friend of GATA-1 (FOG-1) on mast-cell development and differentiation

Abstract

Friend of GATA-1 (FOG-1) is a binding partner of GATA-1, a zinc finger transcription factor with crucial roles in erythroid, megakaryocytic, and mast-cell differentiation. FOG-1 is indispensable for the function of GATA-1 during erythro/megakaryopoiesis, but FOG-1 is not expressed in mast cells. Here, we analyzed the role of FOG-1 in mast-cell differentiation using a combined experimental system with conditional gene expression and in vitro hematopoietic induction of mouse embryonic stem cells. Expression of FOG-1 during the progenitor period inhibited the differentiation of mast cells and enhanced the differentiation of neutrophils. Analysis using a mutant of PU.1, a transcription factor that positively or negatively cooperates with GATA-1, revealed that this lineage skewing was caused by disrupted binding between GATA-1 and PU.1, which is a prerequisite for mast-cell differentiation. However, FOG-1 expression in mature mast cells brought approximately a reversible loss of the mast-cell phenotype. In contrast to the lineage skewing, the loss of the mast-cell phenotype was caused by down-regulation of MITF, a basic helix-loop-helix transcription factor required for mast-cell differentiation and maturation. These results indicate that FOG-1 inhibits mast-cell differentiation in a differentiation stage-dependent manner, and its effects are produced via different molecular mechanisms. IntroductionIn hematopoiesis, more than 10 lineages of mature blood cells are derived from a single hematopoietic stem cell. 1 This process is tightly regulated by extrinsic environmental cues and an intrinsic genetic program. Multipotent hematopoietic cells gradually lose their differentiation ability, giving rise to lineage-restricted hematopoietic progenitors. Once matured, each type of blood cell expresses a set of lineage-specific genes that supports its physiologic functions. Several lineage-specific transcription factors have been identified that control lineage-specific gene expression, and recent studies have demonstrated that these transcription factors cooperate with other transcription factors and cofactors. Moreover, these lineage-specific transcription factors display a variety of biologic functions in a cellular context-dependent manner.The GATA family is the most extensively studied group of hematopoietic transcription factors. All GATA factors recognize a specific DNA sequence known as a GATA box [(A/T)GATA(A/ G)] 2 using the C-finger domain in one of their 2 zinc fingers (N-and C-fingers). GATA-1, a founding member of the GATA family, is highly expressed in erythroid cells, megakaryocytes, mast cells, and eosinophils. 3,4 Gene targeting analyses have shown that GATA-1 is essential for terminal differentiation in erythropoiesis and megakaryopoiesis. [5][6][7][8] Deletion of the upstream regulatory elements in GATA-1 gene leads to reduced GATA-1 expression (GATA-1 low ), 9 indicating that the gene plays a pivotal role in mast-cell differentiation. In GATA-1 low mice, morphologically abnormal mast cells were observed i...

Graded repression of PU.1/Sfpi1 gene transcription by GATA factors regulates hematopoietic cell fate

“…74,93 These lineages lack FOG-1, which may facilitate GATA factor-PU.1 cross-antagonism. 94,95 In this study, Gata2 knockdown enhanced myelopoiesis specifically in cells intrinsically lacking Gata1. Gata2-targeted mice with intact Gata1 alleles were not noted to have increased myelopoiesis, probably because GATA-2 has important actions on hematopoietic progenitor proliferation/survival that are independent of the effects shown here.…”

The role of PU.1 and GATA-1 transcription factors during normal and leukemogenic hematopoiesis

“…36,61 Additional factors that interact with GATA-1 or PU.1 can also modulate the cell-dependent specificity of their activities. The nuclear factor FOG-1 (ZFPM1) is a coactivator of GATA-1 [62][63][64] and is coexpressed with GATA-1 during embryonic development within erythroid and megakaryocytic cells. 65 Surprisingly, in eosinophil and mast cells, FOG-1 can antagonize GATA-1 activity thereby functioning as a corepressor within this cellular-dependent context.…”

The zebrafish reveals dependence of the mast cell lineage on Notch signaling in vivo

“…10 Zebrafish carboxypeptidase a5 (cpa5) was identified as a zebrafish mast cell-specific marker, and gata2 and pu.1 were found to be the key transcription factors required for early mast cell lineage commitment in keeping with studies in mammalian systems. 9,11,12 The Notch signaling pathway is a critical regulator of cell fate determination conserved through evolution. Aberrant Notch signaling is associated with a wide range of human disorders from developmental syndromes to cancer.…”