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 

机构地区：[1]Department of Orthopedics,The Eighth Affiliated Hospital,Sun Yat-sen University,Shenzhen 518003,PR China [2]Shenzhen Key Laboratory of Ankylosing Spondylitis,Shenzhen 518003,PR China [3]Department of Orthopedics,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510120,PR China [4]Center for Biotherapy,The Eighth Affiliated Hospital,Sun Yat-sen University,Shenzhen 518003,PR China

出　　处：《Bone Research》2023年第3期532-547,共16页骨研究（英文版）

基　　金：supported by the National Natural Science Foundation of China [82172385 to H.S., 82172349 to Y.W.];the Key-Area Research and Development Program of Guangdong Province [2019B020236001 to H.S.];the Shenzhen Key Medical Discipline Construction Fund [ZDSYS20190902092851024 to H.S.];the Natural Science Foundation of Guangdong Province [2020A1515010097 to Z.X.];the Shenzhen Outstanding Science and Technology Innovation Talents-Outstanding Youth Fund project [RCYX20210706092106042 to Z.X.];Funding for open access charge:Shenzhen Key Medical Discipline Construction Fund。

摘　　要：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 IIassociated 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 provides an attractive focus and therapeutic target for osteoporosis.

关 键 词：B16 OSTEOPOROSIS OSTEOGENESIS 

分 类 号：R580[医药卫生—内分泌]