Acetyltransferases CBP/p300 Control Transcriptional Switch of β-Catenin and Stat1 Promoting Osteoblast Differentiation,Journal of Bone and Mineral Research

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Acetyltransferases CBP/p300 Control Transcriptional Switch of β-Catenin and Stat1 Promoting Osteoblast Differentiation
Journal of Bone and Mineral Research ( IF 5.1 ) Pub Date : 2023-10-18 , DOI: 10.1002/jbmr.4925
Linlin Zhang _{1,

2,

3} , Kecheng Zhu _{1,

2} , Jingzun Xu _{1,

2} , Xiaojing Chen _{1,

2} , Chunxiang Sheng _{1,

2} , Deng Zhang _{1,

2} , Yuying Yang _{1,

2} , Lihao Sun _{1,

2} , Hongyan Zhao _{1,

2} , Xiao Wang _{1,

2} , Bei Tao _{1,

2} , Libin Zhou _{1,

2} , Jianmin Liu _{1,

2}

Affiliation

CREB-binding protein (CBP) (CREBBP) and p300 (EP300) are multifunctional histone acetyltransferases (HATs) with extensive homology. Germline mutations of CBP or p300 cause skeletal abnormalities in humans and mice. However, the precise roles of CBP/p300 in bone homeostasis remain elusive. Here, we report that conditional knockout of CBP or p300 in osteoblasts results in reduced bone mass and strength due to suppressed bone formation. The HAT activity is further confirmed to be responsible for CBP/p300-mediated osteogenesis using A-485, a selective inhibitor of CBP/p300 HAT. Mechanistically, CBP/p300 HAT governs osteogenic gene expression in part through transcriptional activation of β-catenin and inhibition of Stat1. Furthermore, acetylation of histone H3K27 and the transcription factor Foxo1 are demonstrated to be involved in CBP/p300 HAT-regulated β-catenin and Stat1 transcription, respectively. Taken together, these data identify acetyltransferases CBP/p300 as critical regulators that promote osteoblast differentiation and reveal an epigenetic mechanism responsible for maintaining bone homeostasis. © 2023 American Society for Bone and Mineral Research (ASBMR).

中文翻译：

乙酰转移酶 CBP/p300 控制 β-Catenin 和 Stat1 的转录开关，促进成骨细胞分化

CREB 结合蛋白 (CBP) ( CREBBP ) 和 p300 ( EP300 ) 是具有广泛同源性的多功能组蛋白乙酰转移酶 (HAT)。 CBP 或 p300 的种系突变会导致人类和小鼠骨骼异常。然而，CBP/p300 在骨稳态中的确切作用仍然难以捉摸。在这里，我们报告说，成骨细胞中 CBP 或 p300 的条件性敲除会因骨形成受到抑制而导致骨量和强度降低。使用 CBP/p300 HAT 的选择性抑制剂 A-485 进一步证实 HAT 活性与 CBP/p300 介导的成骨有关。从机制上讲，CBP/p300 HAT 部分通过 β-catenin 的转录激活和 Stat1 的抑制来控制成骨基因表达。此外，组蛋白 H3K27 和转录因子 Foxo1 的乙酰化被证明分别参与 CBP/p300 HAT 调节的 β-catenin 和 Stat1 转录。总而言之，这些数据确定乙酰转移酶 CBP/p300 是促进成骨细胞分化的关键调节因子，并揭示了负责维持骨稳态的表观遗传机制。 © 2023 美国骨与矿物质研究学会 (ASBMR)。

更新日期：2023-10-18

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