期刊
EMBO JOURNAL
卷 41, 期 23, 页码 -出版社
WILEY
DOI: 10.15252/embj.2022111239
关键词
histone acetylation; hypoxia; mesenchymal stem cells; metabolism; osteogenesis
资金
- Max Planck Society
- German Excellence Strategy (CECAD) [EXC 2030-390661388]
- CRUK Programme Foundation [C51061/A27453]
- ERC [ERC819920]
- Alexander von Humboldt Foundation
- EMBO Young Investigator Program
- Onassis foundation graduate fellowship
- Alexander von Humbodlt postdoctoral fellowship
- Marie Sklodowska-Curie grant
- Projekt DEAL
This study reveals the impact of normal oxygen levels on the differentiation of bone-derived mesenchymal stem cells. High oxygen concentration promotes chromatin compaction and histone hypo-acetylation, resulting in osteogenic defects. Additionally, decreased activity of citrate carrier leads to the accumulation of acetyl-CoA inside mitochondria. Restoring cytosolic acetyl-CoA levels rescues the osteogenic defects.
Bone-derived mesenchymal stem cells (MSCs) reside in a hypoxic niche that maintains their differentiation potential. While hypoxia (low oxygen concentration) was reported to critically support stem cell function and osteogenesis, the molecular events triggering changes in stem cell fate decisions in response to normoxia (high oxygen concentration) remain elusive. Here, we study the impact of normoxia on mitochondrial-nuclear communication during stem cell differentiation. We show that normoxia-cultured murine MSCs undergo profound transcriptional alterations which cause irreversible osteogenesis defects. Mechanistically, high oxygen promotes chromatin compaction and histone hypo-acetylation, particularly on promoters and enhancers of osteogenic genes. Although normoxia induces metabolic rewiring resulting in elevated acetyl-CoA levels, histone hypo-acetylation occurs due to the trapping of acetyl-CoA inside mitochondria owing to decreased citrate carrier (CiC) activity. Restoring the cytosolic acetyl-CoA pool remodels the chromatin landscape and rescues the osteogenic defects. Collectively, our results demonstrate that the metabolism-chromatin-osteogenesis axis is perturbed upon exposure to high oxygen levels and identifies CiC as a novel, oxygen-sensitive regulator of the MSC function.
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