Abstract
In red cell development, the differentiation program directed by the transcriptional regulator GATA1 requires signaling by the cytokine erythropoietin, but the mechanistic basis for this signaling requirement has remained unknown. Here we show that erythropoietin regulates GATA1 through protein kinase D activation, promoting histone deacetylase 5 (HDAC5) dissociation from GATA1, and subsequent GATA1 acetylation. Mice deficient for HDAC5 show resistance to anemic challenge and altered marrow responsiveness to erythropoietin injections. In ex vivo studies, HDAC5(-/-) progenitors display enhanced entry into and passage through the erythroid lineage, as well as evidence of erythropoietin-independent differentiation. These results reveal a molecular pathway that contributes to cytokine regulation of hematopoietic differentiation and offer a potential mechanism for fine tuning of lineage-restricted transcription factors by lineage-specific cytokines.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Anemia / enzymology
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Anemia / genetics
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Anemia / pathology
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Animals
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Carbazoles / pharmacology
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Cell Lineage
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Cytokines / physiology
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Enzyme Activation
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Erythroid Precursor Cells / cytology
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Erythroid Precursor Cells / enzymology
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Erythropoiesis / drug effects
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Erythropoiesis / physiology*
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Erythropoietin / pharmacology
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Erythropoietin / therapeutic use
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GATA1 Transcription Factor / physiology*
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Histone Deacetylases / physiology*
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Humans
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Indoles / pharmacology
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Maleimides / pharmacology
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Mice
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Mice, Inbred C57BL
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / physiology*
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Protein Kinase Inhibitors / pharmacology
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Protein Processing, Post-Translational
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RNA Interference
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RNA, Small Interfering / pharmacology
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Signal Transduction
Substances
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2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide
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Carbazoles
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Cytokines
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GATA1 Transcription Factor
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Gata1 protein, mouse
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Indoles
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Maleimides
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Protein Kinase Inhibitors
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RNA, Small Interfering
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Erythropoietin
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Go 6976
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protein kinase C nu
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Protein Kinase C
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Hdac5 protein, mouse
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Histone Deacetylases