Role of p300, a histone acetyltransferase enzyme, in osteoblast differentiation

Krishnan, R.; Sadu, Lakshana; Das, Udipt Ranjan; Satishkumar, Sneha; Adithya, S. Pranav; Saranya, I.; Akshaya, R.L.; Selvamurugan, N.

doi:10.1016/j.diff.2022.02.002

Cited by 9 publications

(5 citation statements)

References 116 publications

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“…Since p300 is a histone acetyltransferase, inhibition of osteoblast differentiation by p300 knockdown may involve histone acetylation [ 25 , 26 ]. Ep300 siRNA was found to decrease histone lactylation and acetylation levels ( Fig 4d , S3 Fig ).…”

Section: Discussionmentioning

confidence: 99%

Lactate-induced histone lactylation by p300 promotes osteoblast differentiation

Minami,

Sasa,

Yamada

et al. 2023

PLoS ONE

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Lactate, which is synthesized as an end product by lactate dehydrogenase A (LDHA) from pyruvate during anaerobic glycolysis, has attracted attention for its energy metabolism and oxidant effects. A novel histone modification-mediated gene regulation mechanism termed lactylation by lactate was recently discovered. The present study examined the involvement of histone lactylation in undifferentiated cells that underwent differentiation into osteoblasts. C2C12 cells cultured in medium with a high glucose content (4500 mg/L) showed increases in marker genes (Runx2, Sp7, Tnap) indicating BMP-2-induced osteoblast differentiation and ALP staining activity, as well as histone lactylation as compared to those cultured in medium with a low glucose content (900 mg/L). Furthermore, C2C12 cells stimulated with the LDH inhibitor oxamate had reduced levels of BMP-2-induced osteoblast differentiation and histone lactylation, while addition of lactate to C2C12 cells cultured in low glucose medium resulted in partial restoration of osteoblast differentiation and histone lactylation. These results indicate that lactate synthesized by LDHA during glucose metabolism is important for osteoblast differentiation of C2C12 cells induced by BMP-2. Additionally, silencing of p300, a possible modifier of histone lactylation, also inhibited osteoblast differentiation and reduced histone lactylation. Together, these findings suggest a role of histone lactylation in promotion of undifferentiated cells to undergo differentiation into osteoblasts.

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Section: Discussionmentioning

confidence: 99%

Lactate-induced histone lactylation by p300 promotes osteoblast differentiation

Minami,

Sasa,

Yamada

et al. 2023

PLoS ONE

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“…RUNX proteins act either as an activator or as a repressor by recruiting other coregulators in the promoter region of target genes. Several coregulators of RUNX2 have been identified, such as p300, SMADs as a coactivator, and histone deacetylase (HDACs), transducing-like enhancer of split (TLE) proteins, mSin3a, and yes-associated protein (YAP) as a corepressor (Zhang et al 2000; Westendorf 2006; Krishnan et al 2022). Whether recruitment is by a coactivator or corepressor depends on the context of transcription factor binding sites and the availability of coactivators to compete with corepressors for binding to the transcription factor (Chen and Courey 2000).…”

Section: Discussionmentioning

confidence: 99%

RUNX2 Regulates Osteoblast Differentiation via the BMP4 Signaling Pathway

et al. 2022

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RUNX2 is a master osteogenic transcription factor, and mutations in RUNX2 cause the inherited skeletal disorder cleidocranial dysplasia (CCD). Studies have revealed that RUNX2 is not only a downstream target of the bone morphogenetic protein (BMP) pathway but can also regulate the expression of BMPs. However, the underlying mechanism of the regulation of BMPs by RUNX2 remains unknown. In this project, we diagnosed a CCD patient with a 7.86-Mb heterozygous deletion on chromosome 6 containing all exons of RUNX2 by multiplex ligation-dependent probe amplification (MLPA) and whole-genome sequencing (WGS). Bone marrow mesenchymal stem cells (BMSCs) were further extracted from patient alveolar bone fragments (CCD-BMSCs), an excellent natural model to explore the possible mechanism. The osteogenic differentiation ability of CCD-BMSCs was severely affected by RUNX2 heterozygous deletion. Also, BMP4 decreased most in BMP ligands, and CHRDL1, a BMP antagonist, was abnormally elevated in CCD-BMSCs. Furthermore, BMP4 treatment essentially rescued the osteogenic capacity of CCD-BMSCs, and RUNX2 overexpression reversed the abnormal expression of BMP4 and CHRDL1. Notably, we constructed CRISPR/Cas9 Runx2+/m MC3T3-E1 cells, which simulated a variant in CCD-BMSCs, to exclude the interference of other gene deletions and the heterogeneity of the genetic background of primary cells, and verified all findings from the CCD-BMSCs. Moreover, the luciferase reporter experiment showed that RUNX2 could inhibit the transcription of CHRDL1. Through immunofluorescence, the inhibitory effect of CHRDL1 on BMP4/Smad signaling was confirmed in MC3T3-E1 cells. These results revealed that RUNX2 regulated the BMP4 pathway by inhibiting CHRDL1 transcription. We collectively identified a novel RUNX2/CHRDL1/BMP4 axis to regulate osteogenic differentiation and noted that BMP4 might be a valuable therapeutic option for treating bone diseases.

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“…These complexes cause changes in chromatin structure and regulate the expression of bone transcription factors such as RUNX2. 59,60 The differentiation of BMSCs into osteoblasts is also regulated by OSX. The OSX acetylation sites K307, K312, and H4K16 are required for osteogenic differentiation, and cAMP response element-binding protein (CREB)-binding proteins are the transcriptional cofactors and HATs that promote OSX acetylation for osteogenesis.…”

Section: Histone Acetylationmentioning

confidence: 99%

“…The cofactor p300 is localized to the promoter of osteogenic genes and can act as a co‐activator with HAT, forming protein complexes with differentially active HAT and acetylate lysine residues of histones H3 and H4 of the nucleosome complex. These complexes cause changes in chromatin structure and regulate the expression of bone transcription factors such as RUNX2 59,60 . The differentiation of BMSCs into osteoblasts is also regulated by OSX.…”

Section: Histone Modificationmentioning

confidence: 99%

Role of epigenetic regulatory mechanisms in age‐related bone homeostasis imbalance

Zhong,

Zhou,

Pan

et al. 2024

The FASEB Journal

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Alterations to the human organism that are brought about by aging are comprehensive and detrimental. Of these, an imbalance in bone homeostasis is a major outward manifestation of aging. In older adults, the decreased osteogenic activity of bone marrow mesenchymal stem cells and the inhibition of bone marrow mesenchymal stem cell differentiation lead to decreased bone mass, increased risk of fracture, and impaired bone injury healing. In the past decades, numerous studies have reported the epigenetic alterations that occur during aging, such as decreased core histones, altered DNA methylation patterns, and abnormalities in noncoding RNAs, which ultimately lead to genomic abnormalities and affect the expression of downstream signaling osteoporosis treatment and promoter of fracture healing in older adults. The current review summarizes the impact of epigenetic regulation mechanisms on age‐related bone homeostasis imbalance.

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Role of p300, a histone acetyltransferase enzyme, in osteoblast differentiation

Cited by 9 publications

References 116 publications

Lactate-induced histone lactylation by p300 promotes osteoblast differentiation

Lactate-induced histone lactylation by p300 promotes osteoblast differentiation

RUNX2 Regulates Osteoblast Differentiation via the BMP4 Signaling Pathway

Role of epigenetic regulatory mechanisms in age‐related bone homeostasis imbalance

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