Regulation of the Myeloperoxidase Enhancer Binding Proteins Pul, C-EBP$\alpha $, -$\beta $, and -$\delta $ during Granulocyte-Lineage Specification

We have compared the molecular architecture and function of the myeloperoxidase upstream enhancer in multipotential versus granulocyte-committed hematopoietic progenitor cells. We show that the enhancer is accessible in multipotential cell chromatin but functionally incompetent before granulocyte co...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1996-10, Vol.93 (20), p.10838-10843
Main Authors: Ford, Anthony M., Bennett, Caroline A., Healy, Lyn E., Towatari, Masayuki, Greaves, Melvyn F., Enver, Tariq
Format: Article
Language:English
Subjects:
B lymphocytes
Cell nucleus
Granulocyte precursor cells
Multipotent stem cells
Myeloid cells
Myeloid progenitor cells
Phosphorylation
Progenitor cells
Protein isoforms
Stem cells
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Summary:We have compared the molecular architecture and function of the myeloperoxidase upstream enhancer in multipotential versus granulocyte-committed hematopoietic progenitor cells. We show that the enhancer is accessible in multipotential cell chromatin but functionally incompetent before granulocyte commitment. Multipotential cells contain both Pu1 and C-EBP$\alpha $ as enhancer-binding activities. Pu1 is unphos-phorylated in both multipotential and granulocyte-committed cells but is phosphorylated in B lymphocytes, raising the possibility that differential phosphorylation may play a role in specifying its lymphoid versus myeloid functions. C-EBP$\alpha $ exists as multiple phosphorylated forms in the nucleus of both multipotential and granulocyte-committed cells. C-EBP$\beta $ is unphos-phorylated and cytoplasmically localized in multipotential cells but exists as a phosphorylated nuclear enhancer-binding activity in granulocyte-committed cells. Granulocyte colony-stimulating factor-induced granulocytic differentiation of multipotential progenitor cells results in activation of C-EBP$\delta $ expression and functional recruitment of C-EBP$\delta $ and C-EBP$\beta $ to the nucleus. Our results implicate Pu1 and the C-EBP family as critical regulators of myeloperoxidase gene expression and are consistent with a model in which a temporal exchange of C-EBP isoforms at the myeloperoxidase enhancer mediates the transition from a primed state in multipotential cells to a transcriptionally active configuration in promyelocytes.
ISSN:0027-8424