The GATA-1 Cofactor FOG-1 Recruits NuRD to Promote Normal Erythroid and Megakaryocyte Development and Maintain Lineage Fidelity by Restricting Mast Cell Gene Expression.

Tissue-specific nuclear factors can establish gene expression patterns in one cell lineage and suppress that of another. GATA-1 and its cofactor FOG-1 (Zfpm1) regulate erythroid and megakaryocyte development by activating and repressing gene transcription. We previously showed that a conserved motif within the N-terminus of FOG-1 binds the Nucleosome Remodeling and Deacetylase (NuRD) co-repressor complex. Here we report that mice bearing FOG-1 point mutations that disrupt the NuRD interaction display mild anemia with splenomegaly and macrothrombocytopenia, a phenotype reminiscent of that observed in animals bearing germline mutations that disrupt the GATA-1/FOG-1 interaction. Microarray studies revealed relatively few changes in gene expression pattern sin mutant erythroid cells and megakaryocytes. Among the most prominent findings was a marked increase in the levels of Gata2 , which is normally silenced in mature erythroid cells. Strikingly, mutant erythroid cells also displayed activation of several genes of the mast cell lineage where FOG-1 is normally extinguished. Furthermore, mutant megakaryocytes misexpressed the same set of mast cell genes, suggesting that NuRD binding by FOG-1 is required to suppress mast cell fate throughout the erythro-megakaryocytic ontogeny. In agreement, prospectively isolated megakaryocytic-erythroid progenitors (MEP) not only exhibited elevated Gata2 and mast cell gene expression, but maintained a multilineage capacity, generating both mast cells and other myeloid lineage cells in culture. Upregulation of mast cell-specific genes is likely the combined consequence of the failure of mutant FOG-1 to function as a repressor and the high levels of GATA-2. Together, these results underscore the importance of the FOG-1-NuRD interaction as an effector of GATA-1 activity. In particular, recruitment of NuRD to GATA-1/FOG-1 regulated genes is required to optimize erythroid and megakaryocytic maturation and restrict a mast cell program in those lineages. More generally, recruitment of NuRD by lineage-specific transcription factors may be a common mechanism to narrow and focus gene expression during tissue maturation.