title: Sp7/Osterix Is Restricted to Bone-Forming Vertebrates where It Acts as a Dlx Co-factor in Osteoblast Specification.
abstract: In extant species, bone formation is restricted to vertebrate species. Sp7/Osterix is a key transcriptional determinant of bone-secreting osteoblasts. We performed Sp7 chromatin immunoprecipitation sequencing analysis identifying a large set of predicted osteoblast enhancers and validated a subset of these in cell culture and transgenic mouse assays. Sp family members bind GC-rich target sequences through their zinc finger domain. Several lines of evidence suggest that Sp7 acts differently, engaging osteoblast targets in Dlx-containing regulatory complexes bound to AT-rich motifs. Amino acid differences in the Sp7 zinc finger domain reduce Sp7's affinity for the Sp family consensus GC-box target; Dlx5 binding maps to this domain of Sp7. The data support a model in which Dlx recruitment of Sp7 to osteoblast enhancers underlies Sp7-directed osteoblast specification. Because an Sp7-like zinc finger variant is restricted to vertebrates, the emergence of an Sp7 member within the Sp family was likely closely coupled to the evolution of bone-forming vertebrates.
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine of the University of Southern California, 1425 San Pablo Street, Los Angeles, CA 90033, USA.
authors.forename: Hironori
authors.initials: H
authors.lastname: Hojo
authors.affiliation: Department of Bioengineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ohba
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine of the University of Southern California, 1425 San Pablo Street, Los Angeles, CA 90033, USA.
authors.forename: Xinjun
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine of the University of Southern California, 1425 San Pablo Street, Los Angeles, CA 90033, USA.
authors.forename: Lick Pui
authors.initials: LP
authors.lastname: Lai
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine of the University of Southern California, 1425 San Pablo Street, Los Angeles, CA 90033, USA. Electronic address: amcmahon@med.usc.edu.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McMahon
mesh_terms: D020856:AT Rich Sequence / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D005075:Biological Evolution; D004247:DNA / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D016678:Genome; D018398:Homeodomain Proteins / Q000378:metabolism*; D051379:Mice; D059372:Nucleotide Motifs / Q000235:genetics; D010006:Osteoblasts / Q000378:metabolism*; D010012:Osteogenesis; D015203:Reproducibility of Results; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014714:Vertebrates / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D004247:DNA
keywords: Dlx; Sp7/Osterix; bone; cis-regulation; evolution; osteoblast specification