CUL4B orchestrates mesenchymal stem cell commitment by epigenetically repressing KLF4 and C/EBPδ.

IF 14.3 1区医学 Q1 CELL & TISSUE ENGINEERING Bone Research Pub Date : 2023-06-02 DOI:10.1038/s41413-023-00263-y

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

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引用次数: 1

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.

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CUL4B通过表观遗传抑制KLF4和C/EBPδ来协调间充质干细胞的承诺。

在骨骼老化和骨质疏松期间，间充质干细胞(MSCs)谱系承诺失调导致骨形成受损以及脂肪生成和成骨生成之间的不平衡。调控MSC承诺的内在细胞机制尚不清楚。在这里，我们确定Cullin 4B (CUL4B)是MSC承诺的关键调节因子。CUL4B在小鼠和人的骨髓间充质干细胞(BMSCs)中表达，并随着年龄的增长而下调。MSCs中Cul4b的条件敲除导致出生后骨骼发育受损，骨量低，骨形成减少。此外，在自然衰老或卵巢切除术后，MSCs中CUL4B的缺失加剧了骨质流失和骨髓脂肪积累。此外，MSCs中CUL4B缺乏会降低骨强度。在机制上，CUL4B分别通过抑制KLF4和C/EBPδ表达促进MSCs成骨和抑制脂肪生成。CUL4B复合体直接与Klf4和Cebpd结合，并从表观遗传学上抑制它们的转录。总的来说，这项研究揭示了cul4b介导的MSCs成骨或成脂承诺的表观遗传调控，这对骨质疏松症具有治疗意义。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bone Research CELL & TISSUE ENGINEERING-

CiteScore

20.00

自引率

4.70%

发文量

289

审稿时长

20 weeks

期刊介绍： Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.