CUL4B orchestrates mesenchymal stem cell commitment by epigenetically repressing KLF4 and C/EBPδ.
CUL4B orchestrates mesenchymal stem cell commitment by epigenetically repressing KLF4 and C/EBPδ.
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DOI：
10.1038/s41413-023-00263-y
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发表时间：
2023-06-02
期刊：
影响因子：
12.7
通讯作者：
Gong, Yaoqin
中科院分区：
文献类型：
--
作者：
Yu, Ruiqi;Han, Hong;Chu, Shuxian;Ding, Yijun;Jin, Shiqi;Wang, Yufeng;Jiang, Wei;Liu, Yuting;Zou, Yongxin;Wang, Molin;Liu, Qiao;Sun, Gongping;Jiang, Baichun;Gong, Yaoqin
间充质干细胞（MSCs）的谱系定型失调导致骨骼衰老和骨质疏松症期间骨形成受损以及脂肪生成和骨生成之间的失衡。调节MSC定型的内在细胞机制尚不清楚。在这里，我们确定了Cullin 4 B（CUL 4 B）作为MSC承诺的关键调节因子。CUL 4 B在骨髓间充质干细胞（BMSC）中表达，并随着小鼠和人类的衰老而下调。条件性敲除MSC中的Cul 4 b导致出生后骨骼发育受损，骨量低，骨形成减少。此外，骨髓间充质干细胞中CUL 4 B的缺失加重了自然衰老过程中或卵巢切除术后的骨丢失和骨髓脂肪积累。此外，MSC中的CUL 4 B缺陷降低了骨强度。CUL 4 B通过抑制KLF 4和C/EBPδ的表达促进MSCs成骨，抑制MSCs成脂。CUL 4 B复合物直接与Klf 4和Cebpd结合，并在表观遗传学上抑制它们的转录。总的来说，这项研究揭示了CUL 4 B介导的表观遗传调控的成骨或成脂承诺的骨髓间充质干细胞，这在骨质疏松症的治疗意义。
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.
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影响因子：
12.4
作者：
Chen Q;Shou P;Zheng C;Jiang M;Cao G;Yang Q;Cao J;Xie N;Velletri T;Zhang X;Xu C;Zhang L;Yang H;Hou J;Wang Y;Shi Y
通讯作者：
Shi Y
间充质干细胞：成骨细胞或脂肪细胞的细胞命运决定及其在骨质疏松症治疗中的应用
影响因子：
5.6
作者：
Hu L;Yin C;Zhao F;Ali A;Ma J;Qian A
通讯作者：
Qian A
DOI：
10.1083/jcb.201008012
发表时间：
2011-03-21
期刊：
The Journal of cell biology
影响因子：
--
作者：
Albers J;Schulze J;Beil FT;Gebauer M;Baranowsky A;Keller J;Marshall RP;Wintges K;Friedrich FW;Priemel M;Schilling AF;Rueger JM;Cornils K;Fehse B;Streichert T;Sauter G;Jakob F;Insogna KL;Pober B;Knobeloch KP;Francke U;Amling M;Schinke T
通讯作者：
Schinke T
影响因子：
3.7
作者：
Benisch P;Schilling T;Klein-Hitpass L;Frey SP;Seefried L;Raaijmakers N;Krug M;Regensburger M;Zeck S;Schinke T;Amling M;Ebert R;Jakob F
通讯作者：
Jakob F
影响因子：
16.6
作者：
Li, Jinbo;Ayoub, Akram;Boyce, Brendan F.
通讯作者：
Boyce, Brendan F.