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

Julie Lessard; Armin Schumacher; Unnur Thorsteinsdottir; Maarten van Lohuizen; Terry Magnuson; Guy Sauvageau

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

Laboratory of Molecular Genetics of Hemopoietic Stem Cells, Clinical Research Institute of Montréal, Montréal, Québec H2W 1R7, Canada; Department of Medicine and Division of Hematology Maisonneuve-Rosemont Hospital, Université de Montréal, Montréal, Québec H3C 3J7, Canada; Department of Molecular and Human Genetics and Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030 USA; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands; Department of Genetics, Case Western Reserve University, Cleveland, Ohio 44106 USA

Abstract

The murine Polycomb-Group (PcG) proteins Eed and Bmi1 govern axial patterning during embryonic development by segment-specific repression of Hox gene expression. The two proteins engage in distinct multimeric complexes that are thought to use a common molecular mechanism to render the regulatory regions of Hox and other downstream target genes inaccessible to transcriptional activators. Beyond axial patterning, Bmi1 is also involved in hemopoiesis because a loss-of-function allele causes a profound decrease in bone marrow progenitor cells. Here, evidence is presented that is consistent with an antagonistic function of eed and Bmi1 in hemopoietic cell proliferation. Heterozygosity for an eed null allele causes marked myelo- and lymphoproliferative defects, indicating that eed is involved in the negative regulation of the pool size of lymphoid and myeloid progenitor cells. This antiproliferative function of eed does not appear to be mediated by Hox genes or the tumor suppressor locus p16^INK4a/p19^ARF because expression of these genes was not altered in eed mutants. Intercross experiments between eed and Bmi1 mutant mice revealed that Bmi1 is epistatic to eed in the control of primitive bone marrow cell proliferation. However, the genetic interaction between the two genes is cell-type specific as the presence of one or two mutant alleles of eed trans-complements the Bmi1-deficiency in pre-B bone marrow cells. These studies thus suggest that hemopoietic cell proliferation is regulated by the relative contribution of repressive (Eed-containing) and enhancing (Bmi1-containing) PcG gene complexes.

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