Acetyltransferases CBP/p300 Control Transcriptional Switch of β-Catenin and Stat1 Promoting Osteoblast Differentiation

Linlin Zhang; Kecheng Zhu; Jingzun Xu; Xiaojing Chen; Chunxiang Sheng; Deng Zhang; Yuying Yang; Lihao Sun; Hongyan Zhao; Xiao Wang; Bei Tao; Libin Zhou; Jianmin Liu

doi:10.1002/jbmr.4925

Acetyltransferases CBP/p300 Control Transcriptional Switch of β-Catenin and Stat1 Promoting Osteoblast Differentiation

J Bone Miner Res. 2023 Dec;38(12):1885-1899. doi: 10.1002/jbmr.4925. Epub 2023 Nov 7.

Authors

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}

Affiliations

¹ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.

PMID: 37850815
DOI: 10.1002/jbmr.4925

Abstract

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).

Keywords: ACETYLATION; BONE FORMATION; CBP/p300; OSTEOBLAST DIFFERENTIATION; STAT1; β-CATENIN.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Animals
CREB-Binding Protein* / genetics
CREB-Binding Protein* / metabolism
Histone Acetyltransferases / genetics
Histone Acetyltransferases / metabolism
Humans
Mice
Osteogenesis / genetics
STAT1 Transcription Factor / metabolism
beta Catenin / metabolism
p300-CBP Transcription Factors* / genetics
p300-CBP Transcription Factors* / metabolism

Substances

beta Catenin
CREB-Binding Protein
Histone Acetyltransferases
p300-CBP Transcription Factors
Stat1 protein, mouse
STAT1 Transcription Factor
Crebbp protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding