Histone deacetylase inhibition promotes osteoblast maturation by altering the histone H4 epigenome and reduces Akt phosphorylation.
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.
From the Department of Orthopedic Surgery.
Amel
A
Dudakovic
Jared M
JM
Evans
Ying
Y
Li
Sumit
S
Middha
Meghan E
ME
McGee-Lawrence
Andre J
AJ
van Wijnen
Jennifer J
JJ
Westendorf
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D060466:Axin Protein / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic / Q000187:drug effects*; D020869:Gene Expression Profiling; D016678:Genome / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism; D000077337:Vorinostat
D060466:Axin Protein; C111729:Axin2 protein, mouse; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007328:Insulin; D010750:Phosphoproteins; D012333:RNA, Messenger; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor; D000077337:Vorinostat; D051057:Proto-Oncogene Proteins c-akt; D006655:Histone Deacetylases
Akt; Bone; Corepressor Transcription; Epigenetics; HDAC; Histone H4; Nherf1; Osteoblasts; Slc9a3r1; Vorinostat