Roles for Intrinsic Disorder and Fuzziness in Generating Context-specific Function in Ultrabithorax, a Hox Transcription Factor

Surprisingly few transcription factors drive animal development relative to the number and diversity of final tissues and body structures. Therefore, most transcription factors must function in more than one tissue. In a famous example, members of the Hox transcription factor family are expressed in contiguous stripes along the anterior/posterior axis during animal development. Individual Hox transcription factors specify all tissues within their expression domain and thus must respond to cellular cues to instigate the correct tissue-specific gene regulatory cascade. We describe how, in the Drosophila Hox protein Ultrabithorax, intrinsically disordered regions implement, regulate and co-ordinate multiple functions, potentially enabling context-specific gene regulation. The large N-terminal disordered domain encodes most of the transcription activation domain and directly impacts DNA binding affinity by the Ubx homeodomain. Similarly, the C-terminal disordered domain alters DNA binding affinity and specificity, interaction with a Hox binding protein and strongly influences both transcription activation and repression. Phosphorylation of the N-terminal disordered domain and alternative splicing of the C-terminal disordered domain could allow the cell to both regulate and co-ordinate DNA binding, protein interactions and transcription regulation. For regulatory mechanisms relying on disorder to continue to be available when Ubx is bound to other proteins or DNA, fuzziness would need to be preserved in these macromolecular complexes. The intrinsically disordered domains in Hox proteins are predicted to be on the very dynamic end of the disorder spectrum, potentially allowing disorder to persist when Ubx is bound to proteins or DNA to regulate the function of these “fuzzy” complexes. Because both intrinsically disordered regions within Ubx have multiple roles, each region may implement several different regulatory mechanisms identified in fuzzy complexes. These intrinsic disorder-based regulatory mechanisms are likely to be critical for allowing Ubx to sense tissue identity and respond by implementing a context-specific gene regulatory cascade.