LRF Is an Essential Downstream Target of GATA1 in Erythroid Development and Regulates BIM-Dependent Apoptosis

• DOI: 10.1016/j.devcel.2009.09.005
• Publication Date: 2009-10-21T12:54:32Z
• Authors: Takahiro Maeda; Keisuke Ito; Taha Merghoub; Laura Poliseno; Robin M. Hobbs; Guocan Wang; Lin Dong; Manami Maeda; Louis C. Dore; Arthur Zelent; Lucio Luzzatto; Julie Teruya-Feld...; Mitchell J. Weiss; Pier Paolo Pandolfi
• Keywords: Erythroid Precursor Cells; 0303 health sciences; Base Sequence; Bcl-2-Like Protein 11; Erythroblasts; Integrases; Gene Expression Profiling; Gene Expression Regulation, Developmental; DEVBIO; Anemia; Apoptosis; Cell Differentiation; Colony-Forming Units Assay; DNA-Binding Proteins; 03 medical and health sciences; GTP-Binding Proteins; Animals; GATA1 Transcription Factor; Genes, Lethal; Apoptosis Regulatory Proteins; Cells, Cultured; Embryonic Stem Cells; Developmental Biology; Cell Proliferation

GATA-1-dependent transcription is essential for erythroid differentiation and maturation. Suppression of programmed cell death is also thought to be critical for this process; however, the link between these two features of erythropoiesis has remained elusive. Here, we show that the POZ-Krüppel family transcription factor, LRF (also known as Zbtb7a/Pokemon), is a direct target of GATA1 and plays an essential antiapoptotic role during terminal erythroid differentiation. We find that loss of Lrf leads to lethal anemia in embryos, due to increased apoptosis of late-stage erythroblasts. This programmed cell death is Arf and p53 independent and is instead mediated by upregulation of the proapoptotic factor Bim. We identify Lrf as a direct repressor of Bim transcription. In strong support of this mechanism, genetic Bim loss delays the lethality of Lrf-deficient embryos and rescues their anemia phenotype. Thus, our data define a key transcriptional cascade for effective erythropoiesis, whereby GATA-1 suppresses BIM-mediated apoptosis via LRF.