TALE transcription factors: Cofactors no more

Exd/PBX, Hth/MEIS and PREP proteins belong to the TALE (three-amino-acid loop extension) superclass of transcription factors (TFs) with an atypical homedomain (HD). Originally discovered as "cofactors" to HOX proteins, revisiting their traditional role in light of genome-wide experiments reveals a strong and reproducible pattern of HOX and TALE co-occupancy across diverse embryonic tissues. While confirming that TALE increases HOX specificity and selectivity in vivo, this wider outlook also reveals novel aspects of HOX:TALE collaboration, namely that HOX TFs generally require pre-bound TALE factors to access their functional binding sites in vivo. In contrast to the restricted expression domains of HOX TFs, TALE factors are largely ubiquitous, and PBX and PREP are expressed at the earliest developmental stages. PBX and MEIS control development of many organs and tissues and their dysregulation is associated with congenital disease and cancer. Accordingly, many instances of TALE cooperation with non HOX TFs have been documented in various systems. The model that emerges from these studies is that TALE TFs create a permissive chromatin platform that is selected by tissue-restricted TFs for binding. In turn, HOX and other tissue-restricted TFs selectively convert a ubiquitous pool of low affinity TALE binding events into high confidence, tissue-restricted binding events associated with transcriptional activation. As a result, TALE:TF complexes are associated with active chromatin and domain/lineage-specific gene activity. TALE ubiquitous expression and broad genomic occupancy, as well as the increasing examples of TALE tissue-specific partners, reveal a universal and obligatory role for TALE in the control of tissue and lineage-specific transcriptional programs, beyond their initial discovery as HOX co-factors.