Essential and Instructive Roles of GATA Factors in Eosinophil Development

Abstract

GATA transcription factors are major regulators of hematopoietic and immune system. Among GATA factors, GATA-1, GATA-2, and GATA-3 play crucial roles in the development of erythroid cells, hematopoietic stem, and progenitor cells, and T helper type 2 (Th2) cells, respectively. A high level of GATA-1 and GATA-2 expression has been observed in eosinophils, but their roles in eosinophil development remain uncertain both in vitro and in vivo. Here we show that enforced expression of GATA-1 in human primary myeloid progenitor cells completely switches myeloid cell fate into eosinophils. Expression of GATA-1 exclusively promotes development and terminal maturation of eosinophils. Functional domain analyses revealed that the COOH-terminal finger is essential for this capacity while the other domains are dispensable. Importantly, GATA-1–deficient mice failed to develop eosinophil progenitors in the fetal liver. On the other hand, GATA-2 also showed instructive capacity comparable to GATA-1 in vitro and efficiently compensated for GATA-1 deficiency in terms of eosinophil development in vivo, indicating that proper accumulation of GATA factors is critical for eosinophil development. Taken together, our findings establish essential and instructive roles of GATA factors in eosinophil development. GATA-1 and GATA-2 could be novel molecular targets for therapeutic approaches to allergic inflammation.

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

“…75 Recent studies have shown that even the simple ectopic expression of both PU.1 and C/EBPa within mesenchymal stem cell-derived fibroblasts is sufficient to activate the myeloid program resulting in an induced macrophage-like phenotype capable of phagocytosis. 76 Finally, enforced expression of GATA-1 leads to reprogramming of myeloblasts and CD34 þ bone marrow cells into eosinophils, 77,78 whereas within mouse granulocyte-monocyte progenitors ectopic GATA-1 can reprogram these cells to adopt erythroid, eosinophilic or basophile-like properties. 79 The above-described observations show that PU.1 and GATA-1 act as 'the motors for reprogramming' and this correlation could be very useful with regard to the application of 'differentiation therapy' whereby re-establishing the correct expression of PU.1 and or GATA-1 within immature leukemic cells, or those attempting to mature into an unwanted lineage should reprogram and differentiate these cells back into their respective cellular lineage.…”

Differential sensitivities of transcription factor target genes underlie cell type-specific gene expression profiles

“…GATA-2 promotes the proliferation and survival of multipotent precursors (2, 3), whereas GATA-1 regulates erythroid, megakaryocyte, and eosinophil differentiation (4)(5)(6)(7). GATA factors engage DNA and coregulators via a dual zinc finger domain (8), and other regions modulate activity (9,10).…”

The evolution of the Th2 immune responses and its relationships with parasitic diseases and allergy

“…Aunque hay células de la inmunidad innata que producen IL-4 e IL-13, los linfocitos son necesarios para la producción de IgE, pues a través de señales por contacto intercelular (CD40/CD40L) inducen el cambio de isotipo en los linfocitos B hacia la cadena pesada épsilon (16). Los teleósteos, que datan de hace más de 300 millones de años, tienen varios genes que codifican para componentes de la respuesta Th2 (17), así como células efectoras (mastocitos, eosinófilos y basófilos) que se activan frente a ciertos estímulos antigénicos de una manera similar a como lo hacen las de los mamíferos (18), lo cual sugiere que desde la aparición de los peces se dio una respuesta inmunitaria parecida a la que conocemos ahora como alérgica.…”

“…Los de origen filogenético más ancestral y mejor caracterizados provienen del pez cebra, Danio rerio, especie que se ha convertido en un buen modelo general para estudiar la respuesta inmunológica de los vertebrados. Balla, et al, aislaron eosinófilos de este pez mediante GATA-2, un marcador celular descrito originalmente en los eosinófilos del ratón (18), y observaron que tenían similitud tanto morfológica como de expresión génica con los eosinófilos de mamíferos. Aunque se detectaron transcriptos de genes que se expresan en los gránulos (ARNasas, principalmente), no se hallaron homólogos de otras proteínas de importancia funcional como la proteína básica mayor y la peroxidasa de eosinófilos.…”