A novel CCDC91 isoform associated with ossification of the posterior longitudinal ligament of the spine works as a non-coding RNA to regulate osteogenic genes
A novel CCDC91 isoform associated with ossification of the posterior longitudinal ligament of the spine works as a non-coding RNA to regulate osteogenic genes
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DOI：
10.1016/j.ajhg.2023.03.004
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发表时间：
2023-04-06
影响因子：
9.8
通讯作者：
Ikegawa, Shiro
中科院分区：
文献类型：
--
作者：
Nakajima, Masahiro;Koido, Masaru;Ikegawa, Shiro
脊柱后纵韧带骨化(OPLL)是导致椎管狭窄和脊髓病的常见顽固性疾病。我们之前已经对OPLL进行了全基因组关联研究，并确定了14个重要的基因座，但它们的生物学意义大多尚不清楚。在这里，我们检查了12p11.22基因座，并在与OPLL相关的新的CCDC91异构体的50UTR中发现了一个变异。利用机器学习预测模型，我们确定新的CCDC91亚型的高表达与rs35098487的G等位基因相关。Rs35098487的风险等位基因在核蛋白结合和转录活性方面表现出较高的亲和力。CCDC91亚型在间充质干细胞和MG-63细胞中的表达下调和过表达表明成骨基因的表达是平行的，其中包括成骨分化的主要转录因子RUNX2。CCDC91亚型与MIR890直接相互作用，MIR890结合RUNX2，降低RUNX2的表达。我们的发现表明，CCDC91异构体通过海绵结合MIR890来增加RUNX2的表达，从而起到竞争内源RNA的作用。
Ossification of the posterior longitudinal ligament of the spine (OPLL) is a common intractable disease that causes spinal stenosis and myelopathy. We have previously conducted genome-wide association studies for OPLL and identified 14 significant loci, but their bio-logical implications remain mostly unclear. Here, we examined the 12p11.22 locus and identified a variant in the 50 UTR of a novel iso-form of CCDC91 that was associated with OPLL. Using machine learning prediction models, we determined that higher expression of the novel CCDC91 isoform was associated with the G allele of rs35098487. The risk allele of rs35098487 showed higher affinity in the binding of nuclear proteins and transcription activity. Knockdown and overexpression of the CCDC91 isoform in mesenchymal stem cells and MG-63 cells showed paralleled expression of osteogenic genes, including RUNX2, the master transcription factor of osteogenic differentiation. The CCDC91 isoform directly interacted with MIR890, which bound to RUNX2 and decreased RUNX2 expression. Our findings suggest that the CCDC91 isoform acts as a competitive endogenous RNA by sponging MIR890 to increase RUNX2 expression.