Makki Nadja, Zhao Jingjing, Liu Zhaoyang, Eckalbar Walter L, Ushiki Aki, Khanshour Anas M, Wu Joe, Rios Jonathan, Gray Ryan S, Wise Carol A, Ahituv Nadav
Department of Anatomy and Cell Biology, University of Florida, College of Medicine, Gainesville, FL, USA.
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
Hum Mol Genet. 2021 Jan 21;29(22):3606-3615. doi: 10.1093/hmg/ddaa242.
Adolescent idiopathic scoliosis (AIS), a sideways curvature of the spine, is the most common pediatric musculoskeletal disorder, affecting ~3% of the population worldwide. However, its genetic bases and tissues of origin remain largely unknown. Several genome-wide association studies (GWAS) have implicated nucleotide variants in non-coding sequences that control genes with important roles in cartilage, muscle, bone, connective tissue and intervertebral disks (IVDs) as drivers of AIS susceptibility. Here, we set out to define the expression of AIS-associated genes and active regulatory elements by performing RNA-seq and chromatin immunoprecipitation-sequencing against H3 lysine 27 acetylation in these tissues in mouse and human. Our study highlights genetic pathways involving AIS-associated loci that regulate chondrogenesis, IVD development and connective tissue maintenance and homeostasis. In addition, we identify thousands of putative AIS-associated regulatory elements which may orchestrate tissue-specific expression in musculoskeletal tissues of the spine. Quantification of enhancer activity of several candidate regulatory elements from our study identifies three functional enhancers carrying AIS-associated GWAS SNPs at the ADGRG6 and BNC2 loci. Our findings provide a novel genome-wide catalog of AIS-relevant genes and regulatory elements and aid in the identification of novel targets for AIS causality and treatment.
青少年特发性脊柱侧凸（AIS）是一种脊柱侧弯，是最常见的儿童肌肉骨骼疾病，影响着全球约3%的人口。然而，其遗传基础和起源组织在很大程度上仍不清楚。几项全基因组关联研究（GWAS）表明，非编码序列中的核苷酸变异控制着在软骨、肌肉、骨骼、结缔组织和椎间盘（IVD）中起重要作用的基因，这些变异是AIS易感性的驱动因素。在这里，我们通过对小鼠和人类这些组织中的H3赖氨酸27乙酰化进行RNA测序和染色质免疫沉淀测序，来确定AIS相关基因和活性调控元件的表达。我们的研究突出了涉及AIS相关基因座的遗传途径，这些途径调节软骨形成、IVD发育以及结缔组织的维持和稳态。此外，我们鉴定出数千个假定的AIS相关调控元件，它们可能协调脊柱肌肉骨骼组织中的组织特异性表达。对我们研究中的几个候选调控元件的增强子活性进行定量分析，确定了三个在ADGRG6和BNC2基因座携带AIS相关GWAS单核苷酸多态性的功能性增强子。我们的研究结果提供了一个全新的全基因组AIS相关基因和调控元件目录，有助于识别AIS病因和治疗的新靶点。
