A conserved motif N-terminal to the DNA-binding domains of myogenic bHLH transcription factors mediates cooperative DNA binding with Pbx-Meis1/Prep1

The t(1;19) chromosomal translocation of pediatric pre-B cell leukemia prod uces chimeric oncoprotein E2a-Pbx1, which contains the N-terminal transacti vation domain of the basic helix-loop-helix (bHLH) transcription factor, E2 a, joined to the majority of the homeodomain protein, Pbx1. There are three Pbx family members, which bind DNA as heterodimers with both broadly expre ssed Meis/Prep1 homeodomain proteins and specifically expressed Hox homeodo main proteins. These Pbx heterodimers can augment the function of transcrip tional activators bound to adjacent elements. In heterodimers, a conserved tryptophan motif in Hox proteins binds a pocket on the surface of the Pbx h omeodomain, while Meis/Prep1 proteins bind an N-terminal Pbx domain, raisin g the possibility that the tryptophan-interaction pocket of the Pbx compone nt of a Pbx-Meis/Prep1 complex is still available to bind tryptophan motifs of other transcription factors bound to flanking elements. Here, we report that Pbx-Meis1/Prep1 binds DNA cooperatively with heterodimers of E2a and MyoD, myogenin, Mrf-4 or Myf-5. As with Hox proteins, a highly conserved tr yptophan motif N-terminal to the DNA-binding domains of each myogenic bHLH family protein is required for cooperative DNA binding with Pbx-Meis1/Prep1 . In vivo, MyoD requires this tryptophan motif to evoke chromatin remodelin g in the Myogenin promoter and to activate Myogenin transcription. Pbx-Meis /Prep1 complexes, therefore, have the potential to cooperate with the myoge nic bHLH proteins in regulating gene transcription.