Binding of Gtf2i-β/δ transcription factors to the ARMS2 gene leads to increased circulating HTRA1 in AMD patients and in vitro
| Autor: | Mao Nakayama, Subhabrata Chakrabarti, Inderjeet Kaur, Margaret M DeAngelis, Taraprasad Das, Toru Noda, Megumi Yamamoto, Daisuke Iejima, Paul N. Baird, Akiko Suga, Robyn H. Guymer, Takeshi Iwata, Yang Pan |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine genetic structures in/del insertion/deletion GWAS genome-wide association studies Biochemistry ALK5 activin receptor-like kinase 5 Macular Degeneration Mice Transcription Factors TFII chemistry.chemical_compound INDEL Mutation Protein Isoforms AMD age-related macular degeneration Gtf2i general transcription factor Iii Promoter Regions Genetic Induced pluripotent stem cell Aged 80 and over OCT optical coherence tomography TGF-β2 transforming growth factor-β2 iPSCs induced pluripotent stem cells Serine Protease HTRA1 High-Temperature Requirement A Serine Peptidase 1 Middle Aged VEGF vascular endothelial growth factor secretion Vascular endothelial growth factor HTRA1 High Temperature Requirement A1 Factor H Female ARMS2 RT-PCR reverse transcription-PCR Research Article ARMS2 Age-Related Maculopathy Susceptibility 2 Gene isoform LD linkage disequilibrium hnRNP-K heterogeneous nuclear ribonucleoprotein K Mice Transgenic Biology CFH complement factor H Polymorphism Single Nucleotide 03 medical and health sciences Transcription Factors TFIII Animals Humans UTR untranslated regions Electrophoretic mobility shift assay age-related macular degeneration Molecular Biology Transcription factor CNV choroidal neovascularization Aged HTRA1 promoter 030102 biochemistry & molecular biology Proteins Cell Biology WB western blotting Molecular biology eye diseases EF1 elongation factor 1 030104 developmental biology GA geographic atrophy chemistry PCV polypoidal choroidal vasculopathy H&E hematoxylin and eosin FCS fetal calf serum sense organs |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1016/j.jbc.2021.100456 |
| Popis: | The disease-initiating molecular events for age-related macular degeneration (AMD), a multifactorial retinal disease affecting many millions of elderly individuals worldwide, are still unknown. Of the over 30 risk and protective loci so far associated with AMD through whole genome-wide association studies (GWAS), the Age-Related Maculopathy Susceptibility 2 (ARMS2) gene locus represents one of the most highly associated risk regions for AMD. A unique insertion/deletion (in/del) sequence located immediately upstream of the High Temperature Requirement A1 (HTRA1) gene in this region confers high risk for AMD. Using electrophoretic mobility shift assay (EMSA), we identified that two Gtf2i-β/δ transcription factor isoforms bind to the cis-element 5'- ATTAATAACC-3' contained in this in/del sequence. The binding of these transcription factors leads to enhanced upregulation of transcription of the secretory serine protease HTRA1 in transfected cells and AMD patient-derived induced pluripotent stem cells (iPSCs). Overexpression of Htra1 in mice using a CAG-promoter demonstrated increased blood concentration of Htra1 protein, caused upregulation of vascular endothelial growth factor (VEGF), and produced a choroidal neovascularization (CNV)-like phenotype. Finally, a comparison of 478 AMD patients to 481 healthy, age-matched controls from Japan, India, Australia, and the USA showed a statistically increased level of secreted HTRA1 blood concentration in AMD patients compared with age-matched controls. Taken together, these results suggest a common mechanism across ethnicities whereby increased systemic blood circulation of secreted serine protease HTRA1 leads to subsequent degradation of Bruch's membrane and eventual CNV in AMD. |
| Databáze: | OpenAIRE |
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