Histone Deacetylase Inhibition Promotes Osteoblast Maturation by Altering the Histone 4 (H4) Epigenome
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE50552 | GEO | 2013/09/04
SECONDARY ACCESSION(S): PRJNA217927
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-09-04 | E-GEOD-50552 | biostudies-arrayexpress
Project description: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 ?, 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.
| S-EPMC3789974 | biostudies-literature
Project description:Suberoylanilidehydroxamic acid (SAHA) significantly increased the expression levels of 127 transcripts and suppressed expression of 130 genes by more than 2-fold within 3 standard deviations of the mean in differentiating MC3T3 sc4 osteoblasts Total RNA was obtained from differentiating MC3T3 sc4 cells treated with SAHA or vehicle (DMSO).
2013-09-04 | E-GEOD-50549 | biostudies-arrayexpress
Project description:ChIP-Seq analysis revealed that suberoylanilidehydroxamic acid (SAHA) increases genome-wide H4 acetylation in differentially regulated genes, except for the 500 bp upstream of transcription start sites (TSS). Chromatin immunoprecipitation (ChIP) with massively parallel high throughput sequencing (Seq) was used to map genome-wide histone H4 acetylation (K4/7/11/15) in the presence or absence of SAHA in differentiating MC3T3 sc4 osteoblasts.
2013-09-04 | E-GEOD-50551 | biostudies-arrayexpress
Project description:Suberoylanilidehydroxamic acid (SAHA) significantly increased the expression levels of 127 transcripts and suppressed expression of 130 genes by more than 2-fold within 3 standard deviations of the mean in differentiating MC3T3 sc4 osteoblasts
2013-09-04 | GSE50549 | GEO
Project description:ChIP-Seq analysis revealed that suberoylanilidehydroxamic acid (SAHA) increases genome-wide H4 acetylation in differentially regulated genes, except for the 500 bp upstream of transcription start sites (TSS).
2013-09-04 | GSE50551 | GEO
Project description:Lymph node (LN) metastases correspond with a worse prognosis in nearly all cancers, yet the occurrence of cancer spreading from LNs remains controversial. Additionally, the mechanisms explaining how cancers survive and exit LNs are largely unknown. Here, we show that breast cancer patients frequently have LN metastases that closely resemble distant metastases. In addition, using a microsurgical model, we show how LN metastasis development and dissemination is regulated by the expression of a chromatin modifier, histone deacetylase 11 (HDAC11). Genetic and pharmacologic blockade of HDAC11 decreases LN tumor growth, yet substantially increases migration and distant metastasis formation. Collectively, we reveal a mechanism explaining how HDAC11 plasticity promotes breast cancer growth as well as dissemination from LNs and suggest caution with the use of HDAC inhibitors.
| S-EPMC6744422 | biostudies-literature
Project description:Nutrigenomics is a rapidly expanding field that elucidates the link between diet-genome interactions. Recent evidence demonstrates that regulation of the epigenome, and in particular inhibition of histone deacetylases (HDACs), impact pathogenetic mechanisms involved in chronic disease. Few studies, to date, have screened libraries of bioactive compounds that act as epigenetic modifiers. This study screened a library of 131 natural compounds to determine bioactive compounds that inhibit Zn-dependent HDAC activity.Using class-specific HDAC substrates, we screened 131 natural compounds for HDAC activity in bovine cardiac tissue. From this screen, we identified 18 bioactive compound HDAC inhibitors. Using our class-specific HDAC substrates, we next screened these 18 bioactive compounds against recombinant HDAC proteins. Consistent with inhibition of HDAC activity, these compounds were capable of inhibiting activity of individual HDAC isoforms. Lastly, we report that treatment of H9c2 cardiac myoblasts with bioactive HDAC inhibitors was sufficient to increase lysine acetylation as assessed via immunoblot.This study provided the first step in identifying multiple bioactive compound HDAC inhibitors. Taken together, this report sets the stage for future exploration of these bioactive compounds as epigenetic regulators to potentially ameliorate chronic disease.
| S-EPMC5508980 | biostudies-other
Project description:Mechanisms that maintain proliferation and delay cell differentiation in the intestinal crypt are not yet fully understood. We have previously shown the implication of histone methylation in the regulation of enterocytic differentiation. In this study, we investigated the role of histone deacetylation as an important epigenetic mechanism that controls proliferation and differentiation of intestinal cells using the histone deacetylase inhibitor suberanilohydroxamic acid (SAHA) on the proliferation and differentiation of human and mouse intestinal cells. Treatment of newly confluent Caco-2/15 cells with SAHA resulted in growth arrest, increased histone acetylation and up-regulation of the expression of intestine-specific genes such as those encoding sucrase-isomaltase, villin and the ion exchanger SLC26A3. Although SAHA has been recently used in clinical trials for cancer treatment, its effect on normal intestinal cells has not been documented. Analyses of small and large intestines of mice treated with SAHA revealed a repression of crypt cell proliferation and a higher expression of sucrase-isomaltase in both segments compared to control mice. Expression of SLC26A3 was also significantly up-regulated in the colons of mice after SAHA administration. Finally, SAHA was also found to strongly inhibit normal human intestinal crypt cell proliferation in vitro. These results demonstrate the important implication of epigenetic mechanisms such as histone acetylation/deacetylation in the regulation of normal intestinal cell fate and proliferation.
| S-EPMC5014201 | biostudies-literature
Project description:ObjectivePatients with epithelial ovarian cancer (EOC) typically present with late-stage disease, posing a significant challenge to treatment. Although taxane and platinum-based chemotherapy plus surgical debulking are initially effective, EOC is marked by frequent recurrence with resistant disease. Immunotherapy represents an appealing treatment paradigm given the ability of immune cells to engage metastatic sites and impede recurrence; however, response rates to checkpoint blockade in ovarian cancer have been disappointing. Here, we tested whether class I HDAC inhibition can promote anti-tumor T cell responses in a spontaneous and nonspontaneous murine model of EOC.MethodsWe used the spontaneous Tg-MISIIR-Tag and nonspontaneous ID8 models of murine ovarian cancer to test this hypothesis. Whole tumor transcriptional changes were assessed using the nCounter PanCancer Mouse Immune Profiling Panel. Changes in select protein expression of regulatory and effector T cells were measured by flow cytometry.ResultsWe found that treatment with the class I HDAC inhibitor entinostat upregulated pathways and genes associated with CD8 T cell cytotoxic function, while downregulating myeloid derived suppressor cell chemoattractants. Suppressive capacity of regulatory T cells within tumors and associated ascites was significantly reduced, reversing the CD8-Treg ratio.ConclusionsOur findings suggest class I HDAC inhibition can promote activation of intratumoral CD8 T cells, potentially by compromising suppressive networks within the EOC tumor microenvironment. In this manner, class I HDAC inhibition might render advanced-stage EOC susceptible to immunotherapeutic treatment modalities.
| S-EPMC7877343 | biostudies-literature