PIAS1 confers DNA-binding specificity on the Msx1 homeoprotein.
The mechanisms by which homeoproteins bind selectively to target genes in vivo have long remained unresolved. Here we report that PIAS1 confers DNA-binding specificity on the Msx1 homeoprotein by regulating its subnuclear localization and proximity to target genes. We demonstrate that the interaction of Msx1 with PIAS1, but not its sumoylation, is required for Msx1 to function as an inhibitor of myoblast differentiation through repression of myogenic regulatory genes, such as MyoD. We find that PIAS1 enables Msx1 to bind selectively to a key regulatory element in MyoD, the CER, in myoblast cells and to distinguish the CER from other nonregulatory TAAT-containing sequences. We show that PIAS1 is required for the appropriate localization and retention of Msx1 at the nuclear periphery in myoblast cells. Furthermore, we demonstrate that myogenic regulatory genes that are repressed by Msx1, namely MyoD and Myf5, are located at the nuclear periphery in myoblast cells. We propose that a key regulatory event for DNA-binding specificity by homeoproteins in vivo is their appropriate targeting to subnuclear compartments where their target genes are located, which can be achieved by cofactors such as PIAS1.
Lee
Hansol
H
Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey 08854, USA.
Quinn
John C
JC
Prasanth
Kannanganattu V
KV
Swiss
Victoria A
VA
Economides
Kyriakos D
KD
Camacho
Marie M
MM
Spector
David L
DL
Abate-Shen
Cory
C
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051957:MSX1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D024510:Muscle Development; D032446:Myoblasts / Q000378:metabolism; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D051957:MSX1 Transcription Factor; C484083:MSX1 protein, human; C484084:Msx1 protein, mouse; C106529:PIAS1 protein, human; C494211:Pias1 protein, mouse; D050828:Protein Inhibitors of Activated STAT; D011994:Recombinant Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D004247:DNA; D044767:Ubiquitin-Protein Ligases