Zebrafish eaf1 suppresses foxo3b expression to modulate transcriptional activity of gata1 and spi1 in primitive hematopoiesis.

Studies implicate a potential role for EAF1 in MLL-ELL induced leukemogenesis; however the biological function of EAF1 in this process remains unknown. In this study, we show that knockdown of zebrafish eaf1 by morpholinos caused serious defects in both primitive and definitive hematopoiesis. Using microarray analysis, we identified foxo3b as a target gene suppressed by eaf1. Ectopic expression of foxo3b in embryos mimicked the phenotypes exhibited in eaf1 morphants, except that foxo3b had no effect on runx1 and c-myb expression while eaf1 morphants did not express these markers in the ventral wall of dorsal aorta. Subsequent experiments showed that a dominant negative form of Foxo3b (dn-foxo3b) partially restored primitive hematopoietic defects in eaf1 morphants, suggesting that foxo3b might serve as a key factor for mediating eaf1 function in primitive hematopoiesis. Furthermore, we observed that foxo3b inhibited the transcriptional activity of gata1 and spi1 through protein-protein interaction. Our findings not only suggest a function of eaf1 on hematopoiesis in vivo, but also reveal a novel regulatory pathway, eaf1-foxo3b-gata1/spi1, that may shed light on the role of EAF1 in MLL-ELL induced leukemogenesis.

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