Mammalian Trithorax and Polycomb-group homologues are antagonistic regulators of homeotic development

Control of cell identity during development is specified in large part by t he unique expression patterns of multiple homeobox-containing (Hox) genes i n specific segments of an embryo. Trithorax and Polycomb-group (Trx-G and P c-G) proteins in Drosophila maintain Hox expression or repression, respecti vely. Mixed lineage leukemia (MLL) is frequently involved in chromosomal tr anslocations associated with acute leukemia and is the one established mamm alian homologue of Trx. Bmi-l was first identified as a collaborator in c-m yc-induced murine lymphomagenesis and is homologous to the Drosophila Pc-G member Posterior sex combs. Here, we note the axial-skeletal transformation s and altered Hox expression patterns of Mll-deficient and Bmi-1-deficient mice were normalized when both MII and Bmi-1 were deleted, demonstrating th eir antagonistic role in determining segmental identity. Embryonic fibrobla sts from MII-deficient compared with Bmi-l-deficient mice demonstrate recip rocal regulation of Hox genes as well as an integrated Hoxc8-lacZ reporter construct. Reexpression of MLL was able to overcome repression, rescuing ex pression of Hoxc8-lacZ in MII-deficient cells. Consistent with this, MLL an d BMI-I display discrete subnuclear colocalization. Although Drosophila Pc- G and Trx-G members have been shown to maintain a previously established tr anscriptional pattern, we demonstrate that MLL can also dynamically regulat e a target Hox gene.