Summary: HOX proteins achieve numerous functions by interacting with the TALE class PBX and MEIS cofactors. In contrast to this established partnership in development and disease, how HOX proteins could interact with PBX and MEIS remains unclear. Here, we present a systematic analysis of HOX/PBX/MEIS interaction properties, scanning all paralog groups with human and mouse HOX proteins in vitro and in live cells. We demonstrate that a previously characterized HOX protein motif known to be critical for HOX-PBX interactions becomes dispensable in the presence of MEIS in all except the two most anterior paralog groups. We further identify paralog-specific TALE-binding sites that are used in a highly context-dependent manner. One of these binding sites is involved in the proliferative activity of HOXA7 in breast cancer cells. Together these findings reveal an extraordinary level of interaction flexibility between HOX proteins and their major class of developmental cofactors. : Dard et al. examine interaction flexibility between HOX proteins and TALE cofactors. The authors identify specific TALE-binding sites in different human HOX proteins. Most of these TALE-binding sites correspond to short motifs that are differently used depending on the DNA-binding site or cell context. Keywords: HOX, PBX, MEIS, BiFC, SLiM, TALE, homeodomain, transcription, protein interaction
