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An Osteoporosis Risk SNP at 1p36.12 Acts as an Allele-Specific Enhancer to Modulate LINC00339 Expression via Long-Range Loop Formation.
Chen, Xiao-Feng; Zhu, Dong-Li; Yang, Man; Hu, Wei-Xin; Duan, Yuan-Yuan; Lu, Bing-Jie; Rong, Yu; Dong, Shan-Shan; Hao, Ruo-Han; Chen, Jia-Bin; Chen, Yi-Xiao; Yao, Shi; Thynn, Hlaing Nwe; Guo, Yan; Yang, Tie-Lin.
Afiliación
  • Chen XF; Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
  • Zhu DL; Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
  • Yang M; Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
  • Hu WX; Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
  • Duan YY; Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
  • Lu BJ; Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
  • Rong Y; Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
  • Dong SS; Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
  • Hao RH; Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
  • Chen JB; Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
  • Chen YX; Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
  • Yao S; Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
  • Thynn HN; Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
  • Guo Y; Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China. Electronic address: guoyan253@mail.xjtu.edu.cn.
  • Yang TL; Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China. Electronic address: yangtielin@mail.xjtu.edu.cn.
Am J Hum Genet ; 102(5): 776-793, 2018 05 03.
Article en En | MEDLINE | ID: mdl-29706346
Genome-wide association studies (GWASs) have reproducibly associated variants within intergenic regions of 1p36.12 locus with osteoporosis, but the functional roles underlying these noncoding variants are unknown. Through an integrative functional genomic and epigenomic analyses, we prioritized rs6426749 as a potential causal SNP for osteoporosis at 1p36.12. Dual-luciferase assay and CRISPR/Cas9 experiments demonstrate that rs6426749 acts as a distal allele-specific enhancer regulating expression of a lncRNA (LINC00339) (∼360 kb) via long-range chromatin loop formation and that this loop is mediated by CTCF occupied near rs6426749 and LINC00339 promoter region. Specifically, rs6426749-G allele can bind transcription factor TFAP2A, which efficiently elevates the enhancer activity and increases LINC00339 expression. Downregulation of LINC00339 significantly increases the expression of CDC42 in osteoblast cells, which is a pivotal regulator involved in bone metabolism. Our study provides mechanistic insight into how a noncoding SNP affects osteoporosis by long-range interaction, a finding that could indicate promising therapeutic targets for osteoporosis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteoporosis / Cromosomas Humanos Par 1 / Regulación de la Expresión Génica / Elementos de Facilitación Genéticos / Polimorfismo de Nucleótido Simple / Alelos / ARN Largo no Codificante / Conformación de Ácido Nucleico Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Am J Hum Genet Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteoporosis / Cromosomas Humanos Par 1 / Regulación de la Expresión Génica / Elementos de Facilitación Genéticos / Polimorfismo de Nucleótido Simple / Alelos / ARN Largo no Codificante / Conformación de Ácido Nucleico Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Am J Hum Genet Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos