Department of Orthopedics, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, China; Key Laboratory of Yunnan Provincial Innovative Application of Traditional Chinese Medicine, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, China; Clinical Medical Research Center, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, China.
The Sixth Affiliated Hospital of Kunming Medical University, Yuxi, Yunnan 653100, China.
J Genet Genomics. 2023 Apr;50(4):264-275. doi: 10.1016/j.jgg.2023.01.009. Epub 2023 Jan 30.
The differentiation imbalance in bone marrow mesenchymal stem cells (BMMSCs) is critical for the development of bone density diseases as the population ages. BMMSCs are precursor cells for osteoblasts and adipocytes; however, the chromatin organization landscapes during BMMSC differentiation remain elusive. In this study, we systematically delineate the four-dimensional genome and dynamic epigenetic atlas of BMMSCs by RNA sequencing, assay for transposase-accessible chromatin sequencing, and high-throughput chromosome conformation capture. The structure analyses reveal 17.5% common and 28.5%-30% specific loops among BMMSCs, osteoblasts, and adipocytes. The subsequent correlation of genome-wide association studies and expression quantitative trait locus (eQTL) data with multi-omics analysis reveal 274 genes and 3634 single nucleotide polymorphisms (SNPs) associated with bone degeneration and osteoporosis (OP). We hypothesize that SNP mutations affect transcription factor (TF) binding sites, thereby affecting changes in gene expression. Furthermore, 26 motifs, 260 TFs, and 291 SNPs are identified to affect the eQTL. Among these genes, DAAM2, TIMP2, and TMEM241 are found to be essential for diseases such as bone degeneration and OP and may serve as potential drug targets.
骨髓间充质干细胞（BMMSCs）的分化失衡是人口老龄化导致骨密度疾病发展的关键。BMMSCs 是成骨细胞和脂肪细胞的前体细胞；然而，BMMSC 分化过程中的染色质组织景观仍然难以捉摸。在这项研究中，我们通过 RNA 测序、转座酶可及染色质测序和高通量染色体构象捕获系统地描绘了 BMMSCs 的四维基因组和动态表观基因组图谱。结构分析显示，BMMSCs、成骨细胞和脂肪细胞之间有 17.5%的共同环和 28.5%-30%的特异性环。随后，全基因组关联研究和表达数量性状基因座（eQTL）数据与多组学分析的相关性揭示了 274 个与骨退化和骨质疏松症（OP）相关的基因和 3634 个单核苷酸多态性（SNP）。我们假设 SNP 突变会影响转录因子（TF）结合位点，从而影响基因表达的变化。此外，还确定了 26 个基序、260 个 TF 和 291 个 SNP 会影响 eQTL。在这些基因中，DAAM2、TIMP2 和 TMEM241 被发现对骨退化和 OP 等疾病至关重要，它们可能成为潜在的药物靶点。
