Functional antagonism of the Polycomb-Group genes eed and Bmi1 in hemopoietic cell proliferation

The murine Polycomb-Group (PcG) proteins Fed and Bmi1 govern axial patterni ng during embryonic development by segment-specific repression of Hox gene expression. The two proteins engage in distinct multimeric complexes that a re thought to use a common molecular mechanism to render the regulatory reg ions of Hox and other downstream target genes inaccessible tot transcriptio nal activators. Beyond axial patterning, Bmi1 is also involved in hemopoies is because a loss-of-function allele causes a profound decrease in bone mar row progenitor cells. Here, evidence is presented that is consistent with a n antagonistic function of eed and Bmi1 in hemopoietic cell proliferation. Heterozygosity for an eed null allele causes marked myelo- and lymphoprolif erative defects, indicating that eed is involved in the negative regulation of the pool size of lymphoid and myeloid progenitor cells. This antiprolif erative function of eed does not appear to be mediated by Hox genes or the tumor suppressor locus g16(INK4a)/p19(ARF) because expression of these gene s was not altered in eed mutants. Intercross experiments between eed and Bm i1 mutant mice revealed that Bmi1 is epistatic to eed in the control of pri mitive bone marrow cell proliferation. However, the genetic interaction bet ween the two genes is cell-type specific as the presence of one or two muta nt alleles of eed trans-complements the Bmi1-deficiency in pre-B bone marro w cells. These studies thus suggest that hemopoietic cell proliferation is regulated by the relative contribution of repressive (Eed-containing) and e nhancing (Bmi1-containing) PcG gene complexes.