Mammalian polyhomeotic homologues Phc2 and Phc1 act in synergy to mediate polycomb repression of Hox genes.
The Polycomb group (PcG) gene products form multimeric protein complexes and contribute to anterior-posterior (A-P) specification via the transcriptional regulation of Hox cluster genes. The Drosophila polyhomeotic genes and their mammalian orthologues, Phc1, Phc2, and Phc3, encode nuclear proteins that are constituents of evolutionarily conserved protein complexes designated class II PcG complexes. In this study, we describe the generation and phenotypes of Phc2-deficient mice. We show posterior transformations of the axial skeleton and premature senescence of mouse embryonic fibroblasts associated with derepression of Hox cluster genes and Cdkn2a genes, respectively. Synergistic actions of a Phc2 mutation with Phc1 and Rnf110 mutations during A-P specification, coimmunoprecipitation of their products from embryonic extracts, and chromatin immunoprecipitation by anti-Phc2 monoclonal antibodies suggest that Hox repression by Phc2 is mediated through the class II PcG complexes, probably via direct binding to the Hox locus. The genetic interactions further reveal the functional overlap between Phc2 and Phc1 and a strict dose-dependent requirement during A-P specification and embryonic survival. Functional redundancy between Phc2 and Phc1 leads us to hypothesize that the overall level of polyhomeotic orthologues in nuclei is a parameter that is critical in enabling the class II PcG complexes to exert their molecular functions.
Isono
Kyo-Ichi
K
RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro, Tsurumi-ku, Yokohama 230-0045, Japan.
Fujimura
Yu-Ichi
Y
Shinga
Jun
J
Yamaki
Makoto
M
O-Wang
Jiyang
J
Takihara
Yoshihiro
Y
Murahashi
Yasuaki
Y
Takada
Yuki
Y
Mizutani-Koseki
Yoko
Y
Koseki
Haruhiko
H
D000818:Animals; D019521:Body Patterning / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009928:Organ Specificity; D063150:Polycomb Repressive Complex 1; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C095822:Hoxb8 protein, mouse; C066476:Pcgf6 protein, mouse; C103827:Phc1 protein, mouse; C501292:Phc2 protein, mouse; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1