title: Competitive binding between Seryl-tRNA synthetase/YY1 complex and NFKB1 at the distal segment results in differential regulation of human vegfa promoter activity during angiogenesis.
abstract: Vascular endothelial growth factor (VEGF) plays a pivotal role in angiogenesis. Previous studies focused on transcriptional regulation modulated by proximal upstream cis-regulatory elements (CREs) of the human vegfa promoter. However, we hypothesized that distal upstream CREs may also be involved in controlling vegfa transcription. In this study, we found that the catalytic domain of Seryl-tRNA synthetase (SerRS) interacted with transcription factor Yin Yang 1 (YY1) to form a SerRS/YY1 complex that negatively controls vegfa promoter activity through binding distal CREs at -4654 to -4623 of vegfa. Particularly, we demonstrated that the -4654 to -4623 segment, which predominantly controls vegfa promoter activity, is involved in competitive binding between SerRS/YY1 complex and NFKB1. We further showed that VEGFA protein and blood vessel development were reduced by overexpression of either SerRS or YY1, but enhanced by the knockdown of either SerRS or yy1. In contrast, these same parameters were enhanced by overexpression of NFKB1, but reduced by knockdown of nfkb1. Therefore, we suggested that SerRS does not bind DNA directly but form a SerRS/YY1 complex, which functions as a negative effector to regulate vegfa transcription through binding at the distal CREs; while NFKB1 serves as a positive effector through competing with SerRS/YY1 binding at the overlapping CREs.
authors.affiliation: Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taiwan.|Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan.
authors.forename: Chuan-Yang
authors.initials: CY
authors.lastname: Fu
authors.affiliation: Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan.
authors.forename: Po-Chun
authors.initials: PC
authors.lastname: Wang
authors.affiliation: Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taiwan.
authors.forename: Huai-Jen
authors.initials: HJ
authors.lastname: Tsai
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D020134:Catalytic Domain; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012714:Serine-tRNA Ligase / Q000737:chemistry / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics*; D050986:YY1 Transcription Factor / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology
chemical_list: D052002:NF-kappa B p50 Subunit; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D050986:YY1 Transcription Factor; D012714:Serine-tRNA Ligase