LRF is an essential downstream target of GATA1 in erythroid development and regulates BIM-dependent apoptosis.
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.
Maeda
Takahiro
T
Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Ito
Keisuke
K
Merghoub
Taha
T
Poliseno
Laura
L
Hobbs
Robin M
RM
Wang
Guocan
G
Dong
Lin
L
Maeda
Manami
M
Dore
Louis C
LC
Zelent
Arthur
A
Luzzatto
Lucio
L
Teruya-Feldstein
Julie
J
Weiss
Mitchell J
MJ
Pandolfi
Pier Paolo
PP
D000740:Anemia / Q000209:etiology; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D001483:Base Sequence; D000072224:Bcl-2-Like Protein 11; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004268:DNA-Binding Proteins / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000378:metabolism; D004900:Erythroblasts / Q000166:cytology* / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000378:metabolism; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000502:physiology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal; D019426:Integrases / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D064547:Myxovirus Resistance Proteins; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D004268:DNA-Binding Proteins; D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D008565:Membrane Proteins; D064547:Myxovirus Resistance Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C117093:Zbtb7a protein, mouse; D008156:Luciferases; C045073:Cre recombinase; D019426:Integrases; D019204:GTP-Binding Proteins