Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518003, P.R. China.
Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, P.R. China.
Hum Mol Genet. 2021 Apr 26;30(3-4):277-293. doi: 10.1093/hmg/ddaa272.
Ankylosing spondylitis (AS) is a rheumatic disease with pathological osteogenesis that causes bony ankylosis and even deformity over time. Mesenchymal stem cells (MSCs) are multipotent stem cells that are the main source of osteoblasts. We previously demonstrated that enhanced osteogenic differentiation of MSCs from AS patients (ASMSCs) is related to pathological osteogenesis in AS. However, the more concrete mechanism needs further exploration. Super enhancers (SEs) are dense clusters of stitched enhancers that control cell identity determination and disease development. Single-nucleotide polymorphisms (SNPs) regulate the formation and interaction of SEs and denote genes accounting for AS susceptibility. Via integrative analysis of multiomic data, including histone 3 lysine 27 acetylation (H3K27ac), chromatin immunoprecipitation sequencing (ChIP-seq), SNPs and RNA sequencing (RNA-seq) data, we discovered a transcription network mediated by AS SNP-adjacent SEs (SASEs) in ASMSCs and identified key genes, such as Toll-like receptor 4 (TLR4), interleukin 18 receptor 1 (IL18R1), insulin-like growth factor binding protein 4 (IGFBP4), transportin 1 (TNPO1) and proprotein convertase subtilisin/kexin type 5 (PCSK5), which are pivotal in osteogenesis and AS pathogenesis. The SASE-regulated network modulates the enhanced osteogenic differentiation of ASMSCs by synergistically activating the PI3K-Akt, NF-kappaB and Hippo signaling pathways. Our results emphasize the crucial role of the SASE-regulated network in pathological osteogenesis in AS, and the preferential inhibition of ASMSC osteogenic differentiation by JQ1 indicates that SEs may be attractive targets in future treatment for new bone formation in AS.
强直性脊柱炎（AS）是一种风湿性疾病，具有病理性成骨作用，随着时间的推移会导致骨强直甚至畸形。间充质干细胞（MSCs）是多能干细胞，是成骨细胞的主要来源。我们之前的研究表明，AS 患者间充质干细胞（ASMSCs）的成骨分化增强与 AS 中的病理性成骨有关。然而，更具体的机制需要进一步探索。超级增强子（SEs）是密集连接的增强子簇，控制细胞身份的确定和疾病的发展。单核苷酸多态性（SNPs）调节 SEs 的形成和相互作用，并表示与 AS 易感性相关的基因。通过整合多组学数据（包括组蛋白 3 赖氨酸 27 乙酰化（H3K27ac）、染色质免疫沉淀测序（ChIP-seq）、SNP 和 RNA 测序（RNA-seq）数据）的分析，我们在 ASMSCs 中发现了一个由 AS SNP 相邻超级增强子（SASEs）介导的转录网络，并确定了关键基因，如 Toll 样受体 4（TLR4）、白细胞介素 18 受体 1（IL18R1）、胰岛素样生长因子结合蛋白 4（IGFBP4）、转运蛋白 1（TNPO1）和脯氨酸内切酶丝氨酸/苏氨酸 5（PCSK5），这些基因在成骨和 AS 发病机制中起着关键作用。SASE 调节的网络通过协同激活 PI3K-Akt、NF-κB 和 Hippo 信号通路，调节 ASMSCs 增强的成骨分化。我们的研究结果强调了 SASE 调节网络在 AS 病理性成骨中的关键作用，以及 JQ1 对 ASMSC 成骨分化的优先抑制作用表明，SEs 可能是未来治疗 AS 新骨形成的有吸引力的靶点。
