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Novel Function in C-terminal Domain of GATA


, : Novel Function in C-terminal Domain of GATA.

Transcription factor GATA1 regulates the expression of a cluster of genes important for hematopoietic cell differentiation toward erythroid and megakaryocytic lineages. Three functional domains have been identified in GATA1, a transactivation domain located in the N terminus (N-TAD) and two zinc finger domains located in the middle of the molecule. Although N-TAD is known as a solitary transactivation domain for GATA1, clinical observations in Down syndrome leukemia suggest that there may be additional transactivation domains. In this study, we found in reporter co-transfection assays that transactivation activity of GATA1 was markedly reduced by deletion of the C-terminal 95 amino acids without significant attenuation of the DNA binding activity or self-association potential. We therefore generated transgenic mouse lines that expressed GATA1 lacking the C-terminal region (GATA1-?CT). When we crossed these transgenic mouse lines to the Gata1-deficient mouse, we found that the GATA1-?CT transgene rescued Gata1-deficient mice from embryonic lethality. The embryos rescued with an almost similar level of GATA1-?CT to endogenous GATA1 developed beyond embryonic 13.5 days, showing severe anemia with accumulation of immature erythroid cells, as was the case for the embryos rescued by endogenous levels of GATA1 lacking N-TAD (GATA1-?NT). Distinct sets of target genes were affected in the embryos rescued by GATA1-?CT and GATA1-?NT. We also found attenuated GATA1 function in cell cycle control of immature megakaryocytes in both lines of rescued embryos. These results thus demonstrate that GATA1 has two independent transactivation domains, N-TAD and C-TAD. Both N-TAD and C-TAD retain redundant as well as specific activities for proper hematopoiesis in vivo.

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