CUL4B orchestrates mesenchymal stem cell commitment by epigenetically repressing KLF4 and C/EBPδ
Ruiqi Yu,
Hong Han,
Shuxian Chu,
Yijun Ding,
Shiqi Jin,
Yufeng Wang,
Wei Jiang,
Yuting Liu,
Yongxin Zou,
Molin Wang,
Qiao Liu,
Gongping Sun,
Baichun Jiang,
Yaoqin Gong
Affiliations
Ruiqi Yu
The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University
Hong Han
The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University
Shuxian Chu
The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University
Yijun Ding
The Key Laboratory of Liquid‒Solid Structural Evolution and Processing of Materials of Ministry of Education and Institute of Liquid Metal and Casting Technology, School of Materials Science and Engineering, Shandong University
Shiqi Jin
The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University
Yufeng Wang
The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University
Wei Jiang
The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University
Yuting Liu
The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University
Yongxin Zou
The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University
Molin Wang
The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University
Qiao Liu
The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University
Gongping Sun
The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University
Baichun Jiang
The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University
Yaoqin Gong
The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University
Abstract Dysregulated lineage commitment of mesenchymal stem cells (MSCs) contributes to impaired bone formation and an imbalance between adipogenesis and osteogenesis during skeletal aging and osteoporosis. The intrinsic cellular mechanism that regulates MSC commitment remains unclear. Here, we identified Cullin 4B (CUL4B) as a critical regulator of MSC commitment. CUL4B is expressed in bone marrow MSCs (BMSCs) and downregulated with aging in mice and humans. Conditional knockout of Cul4b in MSCs resulted in impaired postnatal skeletal development with low bone mass and reduced bone formation. Moreover, depletion of CUL4B in MSCs aggravated bone loss and marrow adipose accumulation during natural aging or after ovariectomy. In addition, CUL4B deficiency in MSCs reduced bone strength. Mechanistically, CUL4B promoted osteogenesis and inhibited adipogenesis of MSCs by repressing KLF4 and C/EBPδ expression, respectively. The CUL4B complex directly bound to Klf4 and Cebpd and epigenetically repressed their transcription. Collectively, this study reveals CUL4B-mediated epigenetic regulation of the osteogenic or adipogenic commitment of MSCs, which has therapeutic implications in osteoporosis.
