SNP-adjacent super enhancer network mediates enhanced osteogenic differentiation of MSCs in ankylosing spondylitis

Abstract

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.

RNA Sequencing Reveals the Expression Profiles of circRNAs and Indicates Hsa_circ_0070562 as a Pro-osteogenic Factor in Bone Marrow-Derived Mesenchymal Stem Cells of Patients With Ankylosing Spondylitis

“…Sustained ER stress in AS bone-derived cells stimulates the activation of the RUNX2 and C/EBP-β genes ( Jo et al, 2017 ). Single-nucleotide polymorphism-adjacent super enhancers modulate the enhanced osteogenic differentiation of AS-BMSCs( Yu et al, 2021 ). However, the function of circRNAs in BMSCs of patients with AS is still unknown and research is needed.…”

“…When new bone forms in the sacroiliac joint, spine and the hip joint, the AS patients generally become ankylosed. Our previous studies documented that long noncoding RNAs and super enhancers are involved in the pathogenesis of osteogenesis in AS ( Xie et al, 2016a ; Yu et al, 2021 ). However, the mechanism of pathological osteogenesis needs to be further elucidated.…”

Heterogeneity induced GZMA-F2R communication inefficient impairs antitumor immunotherapy of PD-1 mAb through JAK2/STAT1 signal suppression in hepatocellular carcinoma

“…The cck8 assay was performed according to the protocol provided by the manufacturer [ 53 ]. Briefly, 2,000 cells were plated in a 96-well tissue culture plate for 8 h and then co-cultured with 8 000 (1:4) CD3 + T cells.…”

Super-Enhancer-Associated Long Non-Coding RNA LINC01485 Promotes Osteogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells by Regulating MiR-619-5p/RUNX2 Axis

“…Considering osteogenic differentiation, Yu et al. ( 28 ) have reported that the single-nucleotide polymorphisms (SNP)-unique ankylosing spondylitis (AS) SNP-adjacent SEs (SASEs)-mRNA network participated in the pathological osteogenesis of AS and enhanced the osteogenic differentiation ability of MSCs from AS patients (ASMSCs). Overall, research regarding the role of SEs in bone-related diseases and osteogenic differentiation has mainly focused on SEs-associated mRNAs but few studies have addressed SEs-associated lncRNAs.…”