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Abstract
A complete understanding of the transcriptional regulation of developmental lineages requires that all relevant factors be identified. Here, we have taken a proteomic approach to identify novel proteins associated with GATA-1, a lineage-restricted zinc finger transcription factor required for terminal erythroid and megakaryocytic maturation. We identify the Krüppel-type zinc finger transcription factor ZBP-89 as being a component of multiprotein complexes involving GATA-1 and its essential cofactor Friend of GATA-1 (FOG-1). Using chromatin immunoprecipitation assays, we show that GATA-1 and ZBP-89 cooccupy cis-regulatory elements of certain erythroid and megakaryocyte-specific genes, including an enhancer of the GATA-1 gene itself. Loss-of-function studies in zebrafish and mice demonstrate an in vivo requirement for ZBP-89 in megakaryopoiesis and definitive erythropoiesis but not primitive erythropoiesis, phenocopying aspects of FOG-1- and GATA-1-deficient animals. These findings identify ZBP-89 as being a novel transcription factor involved in erythroid and megakaryocytic development and suggest that it serves a cooperative function with GATA-1 and/or FOG-1 in a developmental stage-specific manner.
SUPPLEMENTAL MATERIAL
Supplemental material for this article may be found at http://mcb.asm.org/ .
ACKNOWLEDGMENTS
We thank Juanita Merchant for providing ZBP-89 antibody and rat ZBP-89 cDNA, Robert Handin for CD41-eGFP transgenic fish, Sung-Yun Pai for the FLAG-GATA-3 construct, and Stuart Orkin for G1E and G1-ER cells. We also acknowledge Ross Tomaino and Steven Gygi at the Taplin Mass Spectrometry Core Facility at Harvard Medical School for assistance with mass spectrometry.
This work was supported by grants from the NIH (R01 HL 075705 to A.B.C. and R01 DK070838 to B.H.P.), the American Society of Hematology (Junior Faculty Award to A.B.C.), and the March of Dimes (5-FY04-21, 1-FY06-365 to B.H.P.).