Bromodomain Protein BRD4 Accelerates Glucocorticoid Dysregulation of Bone Mass and Marrow Adiposis by Modulating H3K9 and Foxp1
Glucocorticoid provokes bone mass loss and fatty marrow, accelerating osteoporosis development. Bromodomain protein BRD4, an acetyl-histone-binding chromatin reader, regulates stem cell and tissue homeostasis. We uncovered that glucocorticoid inhibited acetyl Lys-9 at the histone 3 (H3K9ac)-binding Runx2 promoter and decreased osteogenic differentiation, whereas bromodomain protein 4 (BRD4) and adipocyte formation were upregulated in bone-marrow mesenchymal progenitor cells. BRD4 knockdown improved H3K9ac occupation at the Runx2 promoter and osteogenesis, but attenuated glucocorticoid-mediated adipocyte formation together with the unaffected H3K9ac-binding PPARγ2 promoter. BRD4 regulated epigenome related to fatty acid metabolism and the forkhead box P1 (Foxp1) pathway, which occupied the PPARγ2 promoter to modulate glucocorticoid-induced adipocytic activity. In vivo, BRD4 inhibitor JQ-1 treatment mitigated methylprednisolone-induced suppression of bone mass, trabecular microstructure, mineral acquisition, and osteogenic differentiation. Foxp1 signaling, marrow fat, and adipocyte formation in glucocorticoid-treated skeleton were reversed upon JQ-1 treatment. Taken together, glucocorticoid-induced H3K9 hypoacetylation augmented BRD4 action to Foxp1, which steered mesenchymal progenitor cells toward adipocytes at the cost of osteogenic differentiation in osteoporotic skeletons. BRD4 inhibition slowed bone mass loss and marrow adiposity. Collective investigations convey a new epigenetic insight into acetyl histone reader BRD4 control of osteogenesis and adipogenesis in skeleton, and highlight the remedial effects of the BRD4 inhibitor on glucocorticoid-induced osteoporosis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
Cells - 9(2020), 6 vom: 19. Juni |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Feng-Sheng [VerfasserIn] |
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| Links: |
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| Themen: |
Acetylation |
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| Anmerkungen: |
Date Completed 07.04.2021 Date Revised 07.04.2021 published: Electronic Citation Status MEDLINE |
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| doi: |
10.3390/cells9061500 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM311540759 |
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| 100 | 1 | |a Wang, Feng-Sheng |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Bromodomain Protein BRD4 Accelerates Glucocorticoid Dysregulation of Bone Mass and Marrow Adiposis by Modulating H3K9 and Foxp1 |
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| 520 | |a Glucocorticoid provokes bone mass loss and fatty marrow, accelerating osteoporosis development. Bromodomain protein BRD4, an acetyl-histone-binding chromatin reader, regulates stem cell and tissue homeostasis. We uncovered that glucocorticoid inhibited acetyl Lys-9 at the histone 3 (H3K9ac)-binding Runx2 promoter and decreased osteogenic differentiation, whereas bromodomain protein 4 (BRD4) and adipocyte formation were upregulated in bone-marrow mesenchymal progenitor cells. BRD4 knockdown improved H3K9ac occupation at the Runx2 promoter and osteogenesis, but attenuated glucocorticoid-mediated adipocyte formation together with the unaffected H3K9ac-binding PPARγ2 promoter. BRD4 regulated epigenome related to fatty acid metabolism and the forkhead box P1 (Foxp1) pathway, which occupied the PPARγ2 promoter to modulate glucocorticoid-induced adipocytic activity. In vivo, BRD4 inhibitor JQ-1 treatment mitigated methylprednisolone-induced suppression of bone mass, trabecular microstructure, mineral acquisition, and osteogenic differentiation. Foxp1 signaling, marrow fat, and adipocyte formation in glucocorticoid-treated skeleton were reversed upon JQ-1 treatment. Taken together, glucocorticoid-induced H3K9 hypoacetylation augmented BRD4 action to Foxp1, which steered mesenchymal progenitor cells toward adipocytes at the cost of osteogenic differentiation in osteoporotic skeletons. BRD4 inhibition slowed bone mass loss and marrow adiposity. Collective investigations convey a new epigenetic insight into acetyl histone reader BRD4 control of osteogenesis and adipogenesis in skeleton, and highlight the remedial effects of the BRD4 inhibitor on glucocorticoid-induced osteoporosis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 650 | 4 | |a Foxp1 | |
| 650 | 4 | |a H3K9 | |
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| 700 | 1 | |a Chen, Yu-Shan |e verfasserin |4 aut | |
| 700 | 1 | |a Ko, Jih-Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Kuo, Chung-Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Ke, Huei-Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Hsieh, Chin-Kuei |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Shao-Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Kuo, Pei-Chen |e verfasserin |4 aut | |
| 700 | 1 | |a Jahr, Holger |e verfasserin |4 aut | |
| 700 | 1 | |a Lian, Wei-Shiung |e verfasserin |4 aut | |
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