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

Abstract

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.This article is protected by copyright. All rights reserved.

3D-printed porous zinc scaffold combined with bioactive serum exosomes promotes bone defect repair in rabbit radius

“…Additionally, Signal Transducer and Activator of Transcription 1 (STAT1) is a member of the STAT protein family and can activate signaling pathways involved in various physiological and pathological responses [ 50 ]. Multiple studies have indicated that STAT1 can induce cellular apoptosis and hinder fracture repair [ 51 , 52 ]. In conclusion, the degradable zinc scaffold/BF Exo composite implants developed in this study enhance the osteogenic, anti-osteoclastic, and pro-angiogenic capabilities during bone defect repair, which may be associated with the regulation of p38/STAT1 by BF Exo.…”

Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis

“…5b ; Table 3 ) 412 . One study reported that conditional knockout of CBP or p300 in osteoblasts inhibited bone formation, resulting in reduced bone mass and strength 412 . Mechanistically, CBP/p300 HAT regulates the expression of osteogenic genes partly by activating β-catenin transcriptionally and suppressing Stat1.…”

“… 411 CBP/P300 Mediates H3K27 acetylation and the activation of Foxo1. 412 Histone deacetylases SIRT1 Enhances Runx2 trans-activation activity. 301 HDAC1 Negatively regulates osteoblast generation by reducing Osx and OCN gene promoters’ H3 and H4 acetyl labeling.…”

“…Besides, CREB-binding protein (CBP) (CREBBP) and p300 (EP300) are multifunctional HATs with broad homology (Fig. 5b ; Table 3 ) 412 . One study reported that conditional knockout of CBP or p300 in osteoblasts inhibited bone formation, resulting in reduced bone mass and strength 412 .…”

Tricarboxylic Acid Cycle Regulation of Metabolic Program, Redox System, and Epigenetic Remodeling for Bone Health and Disease

“…Osteoporosis signs are present in mice upon p300 inhibitor treatment. These two HATs acetylate lysine 27 of histone 3, enhancing β-catenin signaling to promote osteoblastic activity [84]. This HAT interacts with nuclear receptor corepressor and histone deacetylase 3, promoting acetyl histone enrichment at toll-like receptor 4/6 promoters for osteoclast differentiation of macrophages [85].…”