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撰文 江丰 骨质疏松症是一种严重影响身体健康和生活质量的复杂代谢类疾病，表现为骨量减少、骨骼脆性增加，并且易于发生骨折。全世界每3秒就发生一次骨质疏松性骨折，21世纪骨质疏松症发病率已跃居常见疾病第五位。作为人口大国，中国有超过6000万人患有骨质疏松症，预计到2020年将增至2.866亿[1]。骨质疏松症是典型的多基因复杂疾病，其临床诊断表型骨密度( Bone Mineral Density，BMD)的遗传力高达50%~90%[2]。 数十年以来，全基因组关联分析研究（GWAS）已成功鉴定了400余个骨质疏松症易感变异位点[3]，目前亟需探索疾病易感变异的下游调控机制，为临床转化提供潜在靶标。与人类孟德尔疾病相比，骨质疏松症等复杂疾病受多因素共同调控，90%以上的易感变异位于基因组非编码区，其作用机制未知，为破解其致病机制带来了艰巨挑战[4]。非编码区疾病易感变异机制解析是当前遗传学领域的研究热点和难点。 2018年5月3日，西安交通大学生命科学与技术学院杨铁林教授课题组在 发表了题为“An Osteoporosis Risk SNP at 1p36.12 Acts as an Allele-Specific Enhancer to Modulate LINC00339 Expression via Long-Range Loop Formation” 的研究成果。该研究以骨质疏松症为切入点，揭开了基因组“暗物质”非编码区1p36.12基因座的调控秘密：研究发现了染色体1p36.12上一个关键的功能性调控变异——SNP-rs6426749，位于一个增强子上，当其等位基因为G时，能通过结合转录因子TFAP2A来激活这个增强子活性，进而通过染色质成环作用，远距离调控位于600kb 以外的长链非编码 RNA LINC00339的表达。rs6426749-LINC0339 远距离环位于保守的染色质拓扑关联结构域(TAD)内，受转录因子CTCF 调控。LINC0339高表达可显著下调 CDC42基因的表达，进而抑制成骨细胞增殖分化，增加骨质疏松症患病风险。 rs6426749-LINC00339-CDC42-骨质疏松症完整调控模型
该研究首次解析了骨质疏松症易感热点区域1p36.12非编码区 SNP 变异的分子调控机制（如上图），为研究复杂疾病非编码区风险变异调控机制提供了新思路。 西安交通大学生命科学与技术学院杨铁林教授为本文通讯作者，博士研究生陈晓峰和朱东丽为共同第一作者，西安交通大学生命学院是该论文的唯一完成单位。该工作得到了国家自然科学基金、陕西省自然基础研究计划、中央高校基础科研业务费以及西安交通大学“青年拔尖人才支持计划”等项目的支持。2018年6月22号前，该论文可以通过 ScienceDirect 数据库免费浏览和下载全文(https://authors./a/1W~ixgeWqP3j)。
1. 中国健康促进基金会骨质疏松防治中国白皮书编委会: 骨质疏松防治中国白皮书.中华健康管理学杂志2009, 3(3):148-154. 2. Richards JB, Zheng HF, Spector TD: Genetics of osteoporosis from genome-wide association studies: advances and challenges. Nat Rev Genet 2012, 13(8):576-588. 3. Kemp JP, Morris JA, Medina-Gomez C, Forgetta V, Warrington NM, Youlten SE, Zheng J, Gregson CL, Grundberg E, Trajanoska Ket al: Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis. Nat Genet 2017, 49(10):1468-1475. 4. Gallagher MD, Chen-Plotkin AS: The Post-GWAS Era: From Association to Function. American journal of human genetics 2018, 102(5):717-730. 5. MacArthur J, Bowler E, Cerezo M, Gil L, Hall P, Hastings E, Junkins H, McMahon A, Milano A, Morales Jet al: The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog). Nucleic acids research 2017, 45(D1):D896-d901. 相关论文信息 标题 An Osteoporosis Risk SNP at 1p36.12 Acts as an Allele-Specific Enhancer to Modulate LINC00339 Expression via Long-Range Loop Formation 作者 Xiao-Feng Chen, Dong-Li Zhu, Man Yang, Wei-Xin Hu, Yuan-Yuan Duan,Bing-Jie Lu, Yu Rong, Shan-Shan Dong, Ruo-Han Hao, Jia-Bin Chen, Yi-Xiao Chen, Shi Yao, Hlaing NweThynn, Yan Guo ,Tie-Lin Yang 期刊 American Journal of Human Genetics 摘要 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 LINC00339promoter 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. 链接： https://www./science/article/pii/S0002929718300909 |
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