Super enhancers targeting ZBTB16 in osteogenesis protect against osteoporosis

作者：Wenhui Yu, Zhongyu Xie, Jinteng Li, Jiajie Lin, Zepeng Su, Yunshu Che, Feng Ye, Zhaoqiang Zhang, Peitao Xu, Yipeng Zeng, Xiaojun Xu, Zhikun Li, Pei Feng, Rujia Mi, Yanfeng Wu, Huiyong Shen · 发表于：Bone Research · 年份：2023 · DOI：10.1038/s41413-023-00267-8 · 被引用次数：26 · 研究领域：Protein Degradation and Inhibitors、Genomics and Chromatin Dynamics、Cancer-related gene regulation

Abstract As the major cell precursors in osteogenesis, mesenchymal stem cells (MSCs) are indispensable for bone homeostasis and development. However, the primary mechanisms regulating osteogenic differentiation are controversial. Composed of multiple constituent enhancers, super enhancers (SEs) are powerful cis-regulatory elements that identify genes that ensure sequential differentiation. The present study demonstrated that SEs were indispensable for MSC osteogenesis and involved in osteoporosis development. Through integrated analysis, we identified the most common SE-targeted and osteoporosis-related osteogenic gene, ZBTB16 . ZBTB16 , positively regulated by SEs, promoted MSC osteogenesis but was expressed at lower levels in osteoporosis. Mechanistically, SEs recruited bromodomain containing 4 (BRD4) at the site of ZBTB16 , which then bound to RNA polymerase II-associated protein 2 (RPAP2) that transported RNA polymerase II (POL II) into the nucleus. The subsequent synergistic regulation of POL II carboxyterminal domain (CTD) phosphorylation by BRD4 and RPAP2 initiated ZBTB16 transcriptional elongation, which facilitated MSC osteogenesis via the key osteogenic transcription factor SP7. Bone-targeting ZBTB16 overexpression had a therapeutic effect on the decreased bone density and remodeling capacity of Brd4 fl/fl Prx1 -cre mice and osteoporosis (OP) models. Therefore, our study shows that SEs orchestrate the osteogenesis of MSCs by targeting ZBTB16 expression, which provid...