How homeoprotein selectively find its in vivo target

초록

The highly selective biological functions of homeoproteins in vivo are difficult to reconcile with their relatively promiscuous DNA binding specificities in vitro. Here we show PIAS1 and linker histone H1b function as essential components for the selective DNA binding of the Msx1 homeoprotein and demonstrate that their highly specific interactions are required for Msx1 to function as a transcriptional repressor and negative regulator of myoblast differentiation. We found that while H1b provides structural specificity to the Msx1 homeoprotein through its linker DNA binding activity, PIAS1 is required for the localization and retention of Msx1 at the nuclear periphery, where its target gene is located. We propose that the Msx1 homeoprotein finds its target gene in vivo by the combination of: (i) primary sequence elements, with the minimal requirement being a TAAT core recognized by the homeoprotein; (ii) chromatin context, recognized by H1b and its associated proteins; and (iii) “address” within the nuclear compartment controlled by PIAS1. More broadly, we believe this model can readily be extended to explain the DNA binding specificities of other homeoproteins, regardless of whether they utilize H1b and PIAS proteins or other analogous regulatory partners.