Comparative integromics on BMP/GDF family

Abstract

WNT, Notch, FGF, Hedgehog and BMP signaling pathways network together during embryogenesis, tissue regeneration, and carcinogenesis. BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, BMP10, BMP15, AMH, GDF1, GDF2, GDF3, GDF5, GDF6, GDF7, GDF8, GDF9, GDF10, GDF11, and GDF15 are BMP/GDF family genes within the human genome; however, transcriptional regulation of BMP/GDF family members by the canonical WNT signaling pathway remains unclear. We searched for the TCF/LEF-binding site within the promoter region of BMP/GDF family genes by using bioinformatics and human intelligence. Because four TCF/LEF-binding sites were identified within human GDF10 promoter, comparative genomics analyses on GDF10 orthologs were further performed. Chimpanzee GDF10 gene, encoding a 477-amino-acid protein, was identified within NW_112875.1 genome sequence. AY412135.1 was not the correct coding sequence for chimpanzee GDF10. Chimpanzee GDF10 showed 99.2%, 83.2% and 47.4% total amino-acid identity with human GDF10, mouse Gdf10 and human BMP3, respectively. RASGEF1A-GDF10-PRKG1 locus at human chromosome 10q11 and BMP3-PRKG2-RASGEF1B locus at human chromosome 4q21 were paralogous regions with insertions/deletions and recombination. Human GDF10 mRNA was expressed in fetal cochlea, fetal lung, testis, retina, pineal gland, other neural tissues, head and neck tumors, while mouse Gdf10 mRNA was expressed in fetal liver, inner ear, cerebellum, other neural tissues, prostate and blood vessels. Four TCF/LEF-binding sites in human GDF10 promoter were conserved in chimpanzee GDF10 promoter, but not in the mouse Gdf10 promoter; however, another TCF/LEF-binding site occurred in mouse Gdf10 promoter. Four bHLH-binding sites in human GDF10 promoter were conserved in chimpanzee GDF10 promoter, but only one in mouse Gdf10 promoter. Primate GDF10 promoters were divergent from mouse Gdf10 promoter. Because GDF10 was characterized as a potential target of canonical WNT signaling pathway in neural tissues, GDF10 is one of the targets of systems medicine, especially in the field of regenerative medicine.