E47 Binds to PU.1 Inhibiting Its Ability To Bind DNA and Activate Gene Expression.

Abstract

The transciption factor PU.1 is required for the development of macrophages, granulocytes, and B lymphocytes. Additionally its protein concentration in multipotential hematopoietic progenitor cells regulates cell fate decisions with high levels of PU.1 directing myeloid cell fate acquisition and low levels directing B cell fate acquisition. Potentially high levels of PU.1 are required for myeloid development in order to overcome repressive effects of B cell lineage specific factors. The essential B cell factor BSAP (Pax-5) was shown to associate with PU.1 and repress its transactivation activity. Here we investigate whether two other essential B cell factors, E2A and EBF could affect PU.1 activity. We observed that the E2A component, E47, but not EBF could associate with PU.1. Additionally E47 could repress PU.1 dependent transactivation of the M-CSFR promoter and that this repression is mediated by inhibiting PU.1 DNA binding. Exogenous E47 expression in an IL-3 dependent multipotential cell line could block PU.1 induced differentiation and expression of endogenous M-CSF receptor protein. Our data suggests that high PU.1 concentration is required for myeloid development in order to overcome repressive actions of other lineage specific transcriptional regulators such as E47.