We have previously reported the structure of a chromatin remodeling complex (PYR complex) with Ikaros as its DNA binding subunit that is specifically present in adult murine and human hematopoietic cells. We now show that homozygous Ikaros ''knockout'' (null) mice lack the PYR complex, demonstrating the requirement for Ikaros in the formation of the complex on DNA. Heterozygous Ikaros null mice have about half as much PYR complex, indicating a dosage effect for both Ikaros and PYR complex. We also show that Ikaros null mice have multiple hematopoietic cell defects including anemia and megakaryocytic abnormalities, in addition to previously reported lymphoid and stem cell defects. The null mice also have a delay in murine embryonic to adult ␤-globin switching and a delay in human ␥ to ␤ switching, consistent with a previously suggested role for PYR complex in this process. Lastly, cDNA array analyses indicate that several hematopoietic cell-specific genes in all blood lineages are either up-or down-regulated in 14-day embryos from Ikaros null as compared with wild-type mice. These results indicate that Ikaros and PYR complex function together in vivo at many adult hematopoietic cell-specific genes and at intergenic sites, affecting their expression and leading to pleiotropic hematopoietic defects. C hromatin remodeling complexes are associated with both activation and repression of expression of specific eukaryotic genes. SWI͞SNF containing ATPase͞helicase subunits (e.g., BRG1) have been shown to remodel chromatin and activate gene transcription at the ␤-globin locus as well as elsewhere (1, 2). Similarly, NuRD complexes using other ATPase͞helicase subunits (e.g.Mi-2␤) together with histone deacetylases have been associated with chromatin deacetylation and repression of specific gene expression (3). We have recently described a SWI͞SNF and NuRD-containing complex associated with the DNA binding transcription factor Ikaros that is present only in adult hematopoietic cells (4,5). This complex binds to Ikaros-like DNA binding sites including a long polypyrimidine-rich sequence upstream of the human ␦-globin gene and was thus called PYR complex. Deletion of this sequence in a human ␤-locus containing cosmid (carrying sequences from the human A␥ through the adult ␤-globin gene) in transgenic mice results in delayed human ␥-to ␤-globin switching (4).We now have studied Ikaros null mice whose Ikaros gene has been truncated by deletion of the two C-terminal zinc fingers required for Ikaros protein dimerization and function (6, 7). We show that Ikaros null mice completely lack PYR complex, indicating that Ikaros is required for PYR complex formation. In addition, heterozygous null mice have about half as much PYR complex as wild-type mice, indicating a dosage effect for both Ikaros and PYR complex. In this model for evaluating Ikaros and PYR complex function, we find multiple hematopoietic defects including anemia and thrombocytosis, along with previously reported lymphoid and stem cell abnormalities (8). We also show tha...