Takano denoetyiave inhibins promote cae pubmed Abstract J Bone miner Ret 105 ):2254-63, Epub 2005 Aug 8. inhibitors promote osteoblast maturation. Histone schroedet 1 ‘Graduate Progra IM inplay settings y of Minnesota, Minneapolis, USA hd try, Molecular Biology and BIOPhys!°®: Universit M. woatendort. Biochemist . because of their ‘ors cells, and stimulate yn in vitro disease: tum\ cancer and neurological last maturatio or apoptosis of fe osteo! ents for induce growth arres| Abstract ial therapeutic a9} that several HDIs promot HibIs are potent ablities to alter a ditforentiation, In ‘and In calvarial organ cul INTRODUCTION: Histone deacet trials as anticancer agents. ‘some HI ders, Although administered syste ion have not been extensively exar hase inhibition on osteoblast Proll ntly in phase | and I! clinical bed treatments for epilepsy and Dis on osteoblasts and .d the effect of tures. tylase inhibitors (HDI) are currer Dis are also commonly prescr? mmically, the effects of HI ined, In this study, we investigate feration and differentiation. 1s: MC3T3-E1 cells, calvarial-derived primary osteoblasts, and ted with various commercially available HDIs (trichostatin A acid [VPA], or MS-275). The effects of these inhibito ression, Runx2 transcriptional activity, alkaline eralization were determined. Expression levels of ialoprotein, and osteocalcin in pontin, bone si pipolar diso bone format histone deacety! MATERIALS AND METHOD calvarial organ cultures were trea [TSA], sodium butyrate [Nab], valproic cell proliferation, viability, cell cycle prog phosphatase production, and matrix min Pateoblast maturation genes, tYPe | collagen, osteo! response to TSA were measured by quantitative PCR. of histone H3 induced transient RESULTS: Concentrations of HDIs that caused hyperacetylation increases In osteoblast proliferation and viability but did not alter cell cycle profiles. These Concentrations of HDIs also increased the transcriptional activity of Runx2. TSA accelerated alkaline phosphatase production in MC3T3-E1 cells and calvarial organ cultures. In addition, TSA ‘accelerated matrix mineralization and the expression of osteoblast genes, type | collagen, csteopontin, bone sialoprotein, and osteocalcin in MC3T3-E1 cells. CONCLUSIONS: These studies show that histone deacetylase activity regulates osteoblast aitfrentiation and bone formation at least in part by enhancing Runx2-dependent transcriptional activation, Therefore, HDIs are a potentially new class of bone anabolic agents that ma) He useful Inthe treatment of diseases that are associated with bone loss such as osteoporosis a eat ‘patio, 16294278[PubMed - indexed for MEDLINE] 7/18/2012 re Ip \puiwww.nebi.ntm.nih.gov/pubmed/16294278Page 1 of 1 Inhibition of histone acetylation as a tool in bo... {Tissue Eng. 2006] - PubMed - NCBI PubMed Display Settings: Abstract aig A Lede, Tissue Eng. 2006 Oct, 12(10):2927-37. Inhibition of histone acetylation as a tool in bone tissue engineering. de Boer J, Licht R, Bongers M, van der Klundert T, Arends R, van Blitterswijk C. Institute of Biomedical Technology, University of Twente, Enschede, the Netherlands, | deboer@tnw. utwente nl Abstract Our approach to bone tissue engineering is the in vitro expansion and osteogenic differentiation of bone marrow-derived human mesenchymal stem cells (hMSCs) and their subsequent implantation on porous ceramic materials. Current osteogenic differentiation protocols use dexamethasone to initiate the osteogenic process, thus ignoring the multiple signaling pathways that control osteogenesis in vivo. Supporting osteogenesis at multiple stages might further enhance the bone-forming capacity of hMSCs. As reported previously, inhibition of so-called histone deacetylases (HDACs) stimulates osteoblast maturation, and in this report, we investigated whether trichostatin A (TSA), a widely used HDAC inhibitor, can be implemented in bone tissue engineering. We confirmed that TSA treatment of hMSCs results in increased expression of alkaline phosphatase (ALP) with concomitant increase in mineralization. Flow cytometry demonstrated that TSA increases the percentage of ALP-positive hMSCs as well as their average ALP expression level, but the robustness of the response differs between donors, Unfortunately, TSA has a profound negative effect on cell proliferation, so we investigated Whether hMSCs respond to TSA after reaching confluence. Confluent hMSCs on tissue culture Plastic displayed enhanced ALP expression. Therefore, we seeded TSA-treated hMSCs onto ceramic particles and analyzed ectopic bone formation upon implantation in immune-deficient mice. Unfortunately, TSA-treated hMSCs did not display better bone formation in vivo than control cells. Finally, we observed that TSA treatment strongly enhanced bone formation of ex vivo Cultured mouse calvaria, which warrants further exploration of TSA in bone tissue engineering, PMID:17518660[PubMed - indexed for MEDLINE] Publication Types, MeSH Terms, Substances LinkOut - more resources http://www ncbi.nlm.nih.gow/pubmed/17518660 7/18/2012 seem iin ans catamaran aden peemeaenerieies eenieeete iene ene getisien erp[J Biomed Biotechnol, 2011] - PubMed - NCBI Page 1 of 1 Histone deacetylases in neural stem cell. puowed |. [on Display Settings: Abstract ® FREE awn Biomed Biotechnol, 2011;2011:835968. Epub 2011 Aug 7. Histone deacetylases in neural stem cells and induced pluripotent stem cells. ‘Sun G, FuC, Shen , Shi. Department of Neurosciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. Abstract Stem cells have provided great hope for the treatment of a variety of human diseases. However, the molecular mechanisms underlying stem cell pluripotency, self-renewal, and differentiation remain to be unveiled. Epigenetic regulators, including histone deacetylases (HDACs), have been ‘shown to coordinate with cell-intrinsic transcription factors and various signaling pathways to regulate stem cell pluripotency, self-renewal, and fate determination. This paper focuses on the tole of HDACs in the proliferation and neuronal differentiation of neural stem cells and the application of HDAC inhibitors in reprogramming somatic cells to induced pluripotent stem cells (iPSCs). It promises to be an active area of future research. PMID.21845024[PubMed - indexed for MEDLINE] PMCID:PMC3154389 Free PMC Article [Images from t this publication. See all images (2) e ree | text Fi Publication Types, MeSH Terms, Substances, Grant Support LinkOut - more resources http://www.ncbi.nlm.nih.gov/pubmed/21845024 7/8/2012PAAC gomitanne dopheny tbutytate preserves imma... [Int J Mol Med. 2011] - PubMed -N... Page 1 of 2 yaad Display Settings: Abstract PRLMG Med 2011 Deo. 286). 977-83. doi: 10.3892/\jmm.2011.791. Epub 2011 Sep 5. HDAC inhibitor 4-phenylbutyrate preserves immature phenotype of human embryonic midbrain stem cells: implications for the involvement of DNA methyltransferase. Nhand. Adntar M. Ekstrom Ty. Desertrent af Cinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Karolinska University ‘Rowotai, Sona, SE-17176 Stockholm, Sweden, Abstract Call replacement and gene therapy using neural stem cells (NSCs) have been widely touted as a promising treatment for CNS diseases including brain tumors. Histone deacetylase (HDAC) inhibitors have been used to explore mechanisms behind the lineage-specific differentiation of NSCs and as modulators of gene therapy. We have used the human embryonic midbrain stem cell line NGC-407 and the HDAC inhibitor 4-phenylbutyrate (4-PB) to investigate the differentiation from epigenetic perspectives. NGC-407 cells can differentiate into both neurons and glial cells, evidenced by morphological characteristics as well as up-regulation of the respective markers B-tubulin Ill and glial fibrillary acidic protein (GFAP) and simultaneous down- regulation of the NSC-marker nestin. Genomic DNA extracted from the differentiating cells was globally more methylated than that of the proliferating cells. The differentiating cells showed increased expression of the de novo DNA methyltransferase DNMT3B along with strong immunoreactivity in the cell nuclei. When these cells were treated with 4-PB, both the astrocytic and the neuronal differentiation phenotypes were suppressed, which paralleled a substantially weakened DNMT3B immunoreactivity in the cell nuclei. Importantly, 4-PB treatment preserves the immature phenotype of these differentiating cells as indicated by Western blot analysis and immunocytochemical analyses of the NSC markers, nestin and CD133. Nestin becomes entirely degraded 5 days after induction of differentiation, but upon exposure to 4-PB, some of the Gifferentiating cells retain the integrity of nestin and concurrently, CD133 is also up-regulated. Taken together, the data suggests that HDAC activity is necessary for human embryonic NSC differentiation. PMID.218S¢43)PUdMed - indexed for MEDLINE] Publication Types, MeSH Terms, Substances LinkOut - more resources herp:/Awwwanebi.nlm nih gov pubmed’21894430 78/2012 ee eetes dif... [Chin Med J (Engl). 2010] - PubMed - NCBI Page 1 of 1 Histone deacetylase inhibitor promot PubMed Ee eee Display Settings: Abstract Chin Med J (Engl, 2010 Mar 20;123(6):734-8. Histone deacetylase inhibitor promotes differentiation of embryonic stem cells into neural cells in adherent monoculture. Yao X, Zhang JR, Huang HR, Dai LC, Liu QJ, Zhang M. Department of Hepatopancreatobilary Surgery, Huzhou Central Hospital, Huzhou, Zhejiang 313000, China yaoy@mail huptt z| on Abstract BACKGROUND: Embryonic stem (ES) cells poss unlimited self-renewal capacity and the ability to differentiate into cell of all three germ layers in vitro. Induced differentiation of ES cells to neural lineage cells has great potential in basic study of neurogenesis and regeneration therapy of neurodegenerative diseases, Histone deacetylase (HDAC) inhibitors enhance histone acetylation so that globularly activate gene expression and may initiate multiineage differentiation. In this study, we aimed to develop a method to induce the differentiation of ES cells to neural cells, ‘combining HDAC inhibition and neural cell selection. METHODS: In this study, we used HDAC inhibitor sodium butyrate (NaB) to induce the differentiation of mouse embryonic stem cells to neural cells through monolayer culture. After differentiation initiation by histone deacetylase inhibitor sodium butyrate, neural cells were induced and selected with a serum free culture system. RESULTS: Homogeneous neurons without glial cells demonstrated by molecular marker ‘expression were differentiated with the method. The resultant neurons were excitable. CONCLUSION: The method combined differentiation induction effect of HDAC inhibitors and selective culture system to derive neural cells from ES cells, and implied the involvement of epigenetic regulation in neural differentiation. PMID:20368096[PubMed - indexed for MEDLINE] Free full text Publication Types, MeSH Terms, Substances LinkOut - more resources http://www.ncbi.nlm.nih.gov/pubmed/20368096 7/18/2012 eeDifferential requirement of histone acetylase and ... [J Immunol, 2010] «PubMed «NCBL_— Faye 1 of 2 PubMed Display Settings: Abstract Immunol, 2010 Nov 15;185(10):6003-12. Epub 2010 Oct 8. Differential requirement of histone acetylase and deacetylase activities for IRF5-mediated proinflammatory cytokine expression. Feng D, Sangster-Guity N, Stone R, Korezeniewska J, Mancl ME, Fitzgerald-Bocarsly P, Barnes BJ. Department of Biochemistry and Molecular Biology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA. Abstract Recent evidence indicates a new role for histone deacetylases (HDACs) in the activation of genes governing the host immune response. Virus, along with other pathogenic stimuli, triggers an antiviral defense mechanism through the induction of IFN, IFN-stimulated genes, and other proinflammatory cytokines. Many of these genes have been shown to be regulated by transcription factors of the IFN regulatory factor (IRF) family. Recent studies from IRF5 knockout mice have confirmed a critical role for IRFS in virus-induced type | IFN expression and proinflammatory cytokines IL-6, IL-12, and TNF-a; yet, litle is known of the molecular mechanism of IRF5-mediated proinflammatory cytokine expression, In this study, we show that both HDACs and histone acetyltransferases (HATS) associate with IRF5, leading to alterations in its transactivation ability. Using the HDAC inhibitor trichostatin A, we demonstrate that ISRE, IFNA, and IL6 promoters require HDAC activity for transactivation and transcription, whereas TNFa does not. Mapping the interaction of corepressor proteins (HDAC1, silencing mediator of retinoid and thyroid receptorinuclear corepressor of retinoid receptor, and Sin3a) and HATS to IRFS. revealed distinct differences, including the dependence of IRF5 phosphorylation on HAT association resulting in IRFS acetylation. Data presented in this study support a mechanism whereby virus triggers the dynamic conversion of an IRF5-mediated silencing complex to that of an activating complex on promoters of target genes. These data provide the first evidence, to our knowledge, of a tightly controlled transcriptional mechanism whereby IRFS regulates proinflammatory cytokine expression in conjunction with HATs and HDACs. PMID-20935208[PubMed - indexed for MEDLINE] PMCID:PMC3233222 Free PMC Article [Images from this publication. See allimages (6) Free text Bide http://www.ncbi.nlm.nih.gov/pubmed/20935208 7/18/2012 TT TN EEHistone deacetylase inhibitors induce a senesce... [Exp Cell Res. 2004] - PubMed - NCBI Page 1 of 1 i Display Settings: Abstract SEVIER Exp Cell Res. 2004 May 1,295(2):525-38. Histone deacetylase inhibitors induce a senescence-like state in human cells by a p16-dependent mechanism that is independent of a mitotic clock. Munro J, Barr NI, Ireland H, Morrison V, Parkinson EK. Gea Research UK Beatson Laboratories, Beatson Institute for Cancer Research, Bearsden, Glasgow, G61 1BD Abstract We show here that histone deacetylase inhibitors (HDACIs) sodium dibutyrate (SDB) and trichostatin A (TSA) induce a phenotype that has similarities to replicative senescence in human fibroblasts. There was no evidence that SDB accelerated a constitutive cell division counting mechanism as previously suggested because cells pretreated with SDB for three mean population doublings (MPDs) exhibited a similar overall proliferative life span to controls once ‘SDB was withdrawn. SDB-treated cells upregulated the cell cycle inhibitors p24(WAF'1) and p16 (INK4A), but not p14(ARF), in the same sequential order as in senescence and the cells developed biochemical markers of senescence. However, the mechanism of senescence did not involve telomere dysfunction and there was no evidence for any posttransiational modification of 53, The expression of human papillomavirus (HPV) 16 E6 in human fibroblasts or targeted disruption of the p53 and p21(WAF) genes only weakly antagonized HDACI-induced senescence. However, expression of the E7 gene, which inhibits the function of pRb, cooperated with E6 to block SDB-induced senescence completely and human cells deficient in p16(INK4A) (but not p14 (ARF)) were also resistant to SDB-induced senescence, suggesting that the p16(INK4A)/pRb pathway is the major mediator of HDACI-induced senescence in human cells. However, p53-/- mouse fibroblasts were resistant to HDACI-induced senescence, identifying p53 as the major pathway to senescence in this species. PMID: 15093749[PubMed - indexed for MEDLINE] Publication Types, MeSH Terms, Substances LinkOut - more resources http:/www.ncbi.nlm-nih.gov/pubmed/15093749 18/2012