HOX proteins are sequence-specific DNA-binding transcription factors that play a crucial role in the specification of anteroposterior identity in the animal embryo (20, 54). Conservation within the DNA-binding homeodomains results in different HOX proteins recognizing similar regulatory elements with only modest preferences (reviewed in reference 27). High-affinity DNA binding is achieved when HOX proteins are heterodimerized with partners of the PBC family (mammalian PBX, Drosophila Extradenticle [EXD], and Caenorhabditis elegans CEH-20) (55). Mammalian MEIS1 has been shown to independently dimerize with HOX proteins and with PBX (11,57,78). Recently, trimeric complexes encompassing all three homeoproteins, HOX-PBX-MEIS, have also been characterized (77, 79). The MEIS-related protein PREP1, also known as PKNOX1, can additionally form a dimer with PBX, as well as a trimeric complex with HOX and PBX partners (6,7,15,34). While the majority of HOX monomers recognize a DNA core motif of TAAT (23), HOX-PBX, HOX-MEIS, and PBX-MEIS heterodimers recognize larger motifs resulting in a higher affinity and specificity of DNA binding by these homeoproteins (49).A conserved motif with the consensus YPWM is found N terminal to the homeodomain of HOX proteins from paralogous groups 1 to 8. The YPWM motif contacts the PBX homeodomain and is strictly required for cooperative DNA binding by PBX and HOX partners (49,50). A conserved W in HOX proteins from groups 9 and 10 performs a similar function (12).The downstream targets of mammalian HOX proteins have been poorly characterized. The best-characterized targets are some Hox genes known to be positively autoregulated by their own products or cross-regulated by the products of other Hox genes (26,68,69). In these instances, HOX-PBX complexes act as activators of transcription. For example, the Hoxb1 autoregulatory element (ARE) contains three binding sites for HOX-PBX complexes. These sites are required to direct expression of a Hoxb1 transgene in rhombomere 4 (r4) of the developing hindbrain (68).Genetic and molecular studies have provided evidence supporting a negative regulatory role for HOX proteins (43). In the case of decapentaplegic (dpp) regulation in Drosophila, repression by HOX proteins dominates over activation (9). This implies active transcriptional repression by HOX proteins (9,25,46). In addition, in vitro mapping studies have characterized repression domains in different HOX proteins, as well as in the PBX partner (13,45,75). Therefore, HOX proteins may be activators or repressors in a context-dependent manner.By analogy to nuclear receptors, HOX-PBX complexes are likely to achieve transcriptional repression or activation through differential association with coactivators and corepressors (81). One class of coregulators are the histone acetyltransferases (HATs) and the histone deacetylases (HDACs), which modify chromatin as well as nonhistone proteins. The HATs include GCN5, PCAF, CREB-binding protein (CBP)/p300, the steroid receptor coactivator class, and the MY...