Super enhancers targeting ZBTB16 in osteogenesis protect against osteoporosis
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...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-06-01
|
| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-023-00267-8 |
| _version_ | 1797789858232532992 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Wenhui Yu |
| collection | DOAJ |
| description | 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 provides an attractive focus and therapeutic target for osteoporosis. Without SEs located on osteogenic genes, BRD4 is not able to bind to osteogenic identity genes due to its closed structure before osteogenesis. During osteogenesis, histones on osteogenic identity genes are acetylated, and OB-gain SEs appear, enabling the binding of BRD4 to the osteogenic identity gene ZBTB16. RPAP2 transports RNA Pol II from the cytoplasm to the nucleus and guides Pol II to target ZBTB16 via recognition of the navigator BRD4 on SEs. After the binding of the RPAP2-Pol II complex to BRD4 on SEs, RPAP2 dephosphorylates Ser5 at the Pol II CTD to terminate the transcriptional pause, and BRD4 phosphorylates Ser2 at the Pol II CTD to initiate transcriptional elongation, which synergistically drives efficient transcription of ZBTB16, ensuring proper osteogenesis. Dysregulation of SE-mediated ZBTB16 expression leads to osteoporosis, and bone-targeting ZBTB16 overexpression is efficient in accelerating bone repair and treating osteoporosis. |
| first_indexed | 2024-03-13T01:56:31Z |
| format | Article |
| id | doaj.art-8f71368932f247768d150f3bf5cc63fd |
| institution | Directory Open Access Journal |
| issn | 2095-6231 |
| language | English |
| last_indexed | 2024-03-13T01:56:31Z |
| publishDate | 2023-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj.art-8f71368932f247768d150f3bf5cc63fd2023-07-02T11:10:08ZengNature Publishing GroupBone Research2095-62312023-06-0111111610.1038/s41413-023-00267-8Super enhancers targeting ZBTB16 in osteogenesis protect against osteoporosisWenhui Yu0Zhongyu Xie1Jinteng Li2Jiajie Lin3Zepeng Su4Yunshu Che5Feng Ye6Zhaoqiang Zhang7Peitao Xu8Yipeng Zeng9Xiaojun Xu10Zhikun Li11Pei Feng12Rujia Mi13Yanfeng Wu14Huiyong Shen15Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen UniversityDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityCenter for Biotherapy, The Eighth Affiliated Hospital, Sun Yat-sen UniversityCenter for Biotherapy, The Eighth Affiliated Hospital, Sun Yat-sen UniversityShenzhen Key Laboratory of Ankylosing SpondylitisDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityAbstract 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 provides an attractive focus and therapeutic target for osteoporosis. Without SEs located on osteogenic genes, BRD4 is not able to bind to osteogenic identity genes due to its closed structure before osteogenesis. During osteogenesis, histones on osteogenic identity genes are acetylated, and OB-gain SEs appear, enabling the binding of BRD4 to the osteogenic identity gene ZBTB16. RPAP2 transports RNA Pol II from the cytoplasm to the nucleus and guides Pol II to target ZBTB16 via recognition of the navigator BRD4 on SEs. After the binding of the RPAP2-Pol II complex to BRD4 on SEs, RPAP2 dephosphorylates Ser5 at the Pol II CTD to terminate the transcriptional pause, and BRD4 phosphorylates Ser2 at the Pol II CTD to initiate transcriptional elongation, which synergistically drives efficient transcription of ZBTB16, ensuring proper osteogenesis. Dysregulation of SE-mediated ZBTB16 expression leads to osteoporosis, and bone-targeting ZBTB16 overexpression is efficient in accelerating bone repair and treating osteoporosis.https://doi.org/10.1038/s41413-023-00267-8 |
| spellingShingle | 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 Super enhancers targeting ZBTB16 in osteogenesis protect against osteoporosis Bone Research |
| title | Super enhancers targeting ZBTB16 in osteogenesis protect against osteoporosis |
| title_full | Super enhancers targeting ZBTB16 in osteogenesis protect against osteoporosis |
| title_fullStr | Super enhancers targeting ZBTB16 in osteogenesis protect against osteoporosis |
| title_full_unstemmed | Super enhancers targeting ZBTB16 in osteogenesis protect against osteoporosis |
| title_short | Super enhancers targeting ZBTB16 in osteogenesis protect against osteoporosis |
| title_sort | super enhancers targeting zbtb16 in osteogenesis protect against osteoporosis |
| url | https://doi.org/10.1038/s41413-023-00267-8 |
| work_keys_str_mv | AT wenhuiyu superenhancerstargetingzbtb16inosteogenesisprotectagainstosteoporosis AT zhongyuxie superenhancerstargetingzbtb16inosteogenesisprotectagainstosteoporosis AT jintengli superenhancerstargetingzbtb16inosteogenesisprotectagainstosteoporosis AT jiajielin superenhancerstargetingzbtb16inosteogenesisprotectagainstosteoporosis AT zepengsu superenhancerstargetingzbtb16inosteogenesisprotectagainstosteoporosis AT yunshuche superenhancerstargetingzbtb16inosteogenesisprotectagainstosteoporosis AT fengye superenhancerstargetingzbtb16inosteogenesisprotectagainstosteoporosis AT zhaoqiangzhang superenhancerstargetingzbtb16inosteogenesisprotectagainstosteoporosis AT peitaoxu superenhancerstargetingzbtb16inosteogenesisprotectagainstosteoporosis AT yipengzeng superenhancerstargetingzbtb16inosteogenesisprotectagainstosteoporosis AT xiaojunxu superenhancerstargetingzbtb16inosteogenesisprotectagainstosteoporosis AT zhikunli superenhancerstargetingzbtb16inosteogenesisprotectagainstosteoporosis AT peifeng superenhancerstargetingzbtb16inosteogenesisprotectagainstosteoporosis AT rujiami superenhancerstargetingzbtb16inosteogenesisprotectagainstosteoporosis AT yanfengwu superenhancerstargetingzbtb16inosteogenesisprotectagainstosteoporosis AT huiyongshen superenhancerstargetingzbtb16inosteogenesisprotectagainstosteoporosis |