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Histone Deacetylase Inhibition Promotes Osteoblast Maturation by Altering the Histone H4 Epigenome and Reduces Akt Phosphorylation
- Source :
- Journal of Biological Chemistry. 288:28783-28791
- Publication Year :
- 2013
- Publisher :
- Elsevier BV, 2013.
-
Abstract
- Bone has remarkable regenerative capacity, but this ability diminishes during aging. Histone deacetylase inhibitors (HDIs) promote terminal osteoblast differentiation and extracellular matrix production in culture. The epigenetic events altered by HDIs in osteoblasts may hold clues for the development of new anabolic treatments for osteoporosis and other conditions of low bone mass. To assess how HDIs affect the epigenome of committed osteoblasts, MC3T3 cells were treated with suberoylanilide hydroxamic acid (SAHA) and subjected to microarray gene expression profiling and high-throughput ChIP-Seq analysis. As expected, SAHA induced differentiation and matrix calcification of osteoblasts in vitro. ChIP-Seq analysis revealed that SAHA increased histone H4 acetylation genome-wide and in differentially regulated genes, except for the 500 bp upstream of transcriptional start sites. Pathway analysis indicated that SAHA increased the expression of insulin signaling modulators, including Slc9a3r1. SAHA decreased phosphorylation of insulin receptor β, Akt, and the Akt substrate FoxO1, resulting in FoxO1 stabilization. Thus, SAHA induces genome-wide H4 acetylation and modulates the insulin/Akt/FoxO1 signaling axis, whereas it promotes terminal osteoblast differentiation in vitro.
- Subjects :
- Chromatin Immunoprecipitation
Sodium-Hydrogen Exchangers
Cellular differentiation
FOXO1
Biology
Hydroxamic Acids
Biochemistry
Histone Deacetylases
Cell Line
Epigenesis, Genetic
Histones
Histone H4
Mice
Axin Protein
medicine
Animals
Insulin
Gene Regulation
RNA, Messenger
Phosphorylation
Promoter Regions, Genetic
Molecular Biology
Protein kinase B
Vorinostat
Genome
Osteoblasts
Gene Expression Profiling
Reproducibility of Results
Acetylation
Cell Differentiation
Osteoblast
Cell Biology
Epigenome
Phosphoproteins
Histone Deacetylase Inhibitors
medicine.anatomical_structure
Cancer research
Histone deacetylase
Proto-Oncogene Proteins c-akt
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 288
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....1cfdc61641e725f0573bcfe7476882b5