The Experts below are selected from a list of 43233 Experts worldwide ranked by ideXlab platform
Andre Fischer - One of the best experts on this subject based on the ideXlab platform.
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reducing HDAC6 ameliorates cognitive deficits in a mouse model for alzheimer s disease
Embo Molecular Medicine, 2013Co-Authors: Nambirajan Govindarajan, Pooja Rao, Susanne Burkhardt, Farahnaz Sananbenesi, Oliver M Schluter, Frank Bradke, Andre FischerAbstract:Histone deacetylases (HDACs) are currently being discussed as promising therapeutic targets to treat neurodegenerative diseases. However, the role of specific HDACs in cognition and neurodegeneration remains poorly understood. Here, we investigate the function of HDAC6, a class II member of the HDAC superfamily, in the adult mouse brain. We report that mice lacking HDAC6 are cognitively normal but reducing endogenous HDAC6 levels restores learning and memory and α-tubulin acetylation in a mouse model for Alzheimer's disease (AD). Our data suggest that this therapeutic effect is, at least in part, linked to the observation that loss of HDAC6 renders neurons resistant to amyloid-β-mediated impairment of mitochondrial trafficking. Thus, our study suggests that targeting HDAC6 could be a suitable strategy to ameliorate cognitive decline observed in AD.
Paul A Marks - One of the best experts on this subject based on the ideXlab platform.
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HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation
Clinical Cancer Research, 2008Co-Authors: Raphael B Parmigiani, Gisela Ventaperez, Hediye Erdjumentbromage, Mariana Yaneva, Paul Tempst, Paul A MarksAbstract:A19 Eighteen histone deacetylases (HDAC) are present in humans, categorized into two groups: zinc dependent enzymes (HDAC1-11) and NAD+ dependent enzymes (Sirtuins 1-7). Among zinc dependent HDACs, HDAC6 is unique. It has a cytoplasmic localization, two catalytic sites, an ubiquitin binding site and selectively deacetylases α-tubulin and HSP90. Here we report the novel discovery that the redox regulatory proteins, peroxiredoxin (Prx) I and Prx II are specific targets of HDAC6. Prx are antioxidants enzymes whose main function is H2O2 reduction. Prx are elevated in many cancers and neurodegenerative diseases. The acetylated form of Prx accumulates in the absence of an active HDAC6. Acetylation of Prx increases its reducing activity, its resistance to super oxidation and its resistance to transition to high molecular weight complexes. Thus, HDAC6 and Prx are targets for modulating intracellular redox status in therapeutic strategies for disorders as disparate as cancers and neurodegenerative diseases.
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HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Raphael B Parmigiani, Gisela Ventaperez, Hediye Erdjumentbromage, Mariana Yaneva, Paul Tempst, Paul A MarksAbstract:Eighteen histone deacetylases (HDACs) are present in humans, categorized into two groups: zinc-dependent enzymes (HDAC1–11) and NAD+-dependent enzymes (sirtuins 1–7). Among zinc-dependent HDACs, HDAC6 is unique. It has a cytoplasmic localization, two catalytic sites, a ubiquitin-binding site, and it selectively deacetylases α-tubulin and Hsp90. Here, we report the discovery that the redox regulatory proteins, peroxiredoxin (Prx) I and Prx II are specific targets of HDAC6. Prx are antioxidants enzymes whose main function is H2O2 reduction. Prx are elevated in many cancers and neurodegenerative diseases. The acetylated form of Prx accumulates in the absence of an active HDAC6. Acetylation of Prx increases its reducing activity, its resistance to superoxidation, and its resistance to transition to high-molecular-mass complexes. Thus, HDAC6 and Prx are targets for modulating intracellular redox status in therapeutic strategies for disorders as disparate as cancers and neurodegenerative diseases.
Donald R Menick - One of the best experts on this subject based on the ideXlab platform.
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Abstract 238: Class I HDAC inhibition prevents Ncx1 upregulation by stabilizing an HDAC5-HDAC1/Sin3a Repressor Complex during cardiac hypertrophy.
Circulation Research, 2013Co-Authors: Sabina Wang, Lillianne G Harris, Santhosh K Mani, Donald R MenickAbstract:Cardiac hypertrophy is often associated with the activation of signaling pathways that perpetuate altered calcium efflux and influx. One gene that is upregulated and contributes to altered intracellular calcium concentrations and worsening contractility during cardiac hypertrophy is the Sodium Calcium Exchanger ( Ncx1 ). Molecular studies implicate histone deacetylases (HDACs) in possibly regulating the expression of this gene. Our recent work reveals that HDAC1, HDAC5 and Sin3a interact and are recruited to the Ncx1 promoter through the Nkx2.5 transcription factor. Interestingly, we observed greater associated/interaction of the HDAC1-HDAC5/Sin3a repressor complex upon broad HDAC inhibition. Taken together, we hypothesized that HDAC inhibition, stabilizes an HDAC1-HDAC5/Sin3a repressor complex during cardiac hypertrophy. We addressed this hypothesis by treating isolated adult cardiomyocytes with class specific HDAC inhibitors since HDAC1 is a Class I HDAC and HDAC5 is a Class IIa HDAC. Co-Immunoprecipitation (Co-IP) revealed a greater association of repressor complex molecules in the presence of Entinostat, a Class I HDAC inhibitor compared to both non-treated control and TSA, a broad HDAC inhibitor (n=3). These works show enhanced recruitment Sin3a (co-repressor) at the proximal promoter of NCX1 as demonstrated by Chromatin-Immunoprecipitation (ChIP) (n=3). To test whether these observations translated into in vivo models, we subjected mice to transaortic constriction (TAC) to induce hypertrophy. In this model, Co-IP revealed results that similar to our in vitro studies with greater immuno- detection of repressor complex component, Sin3a after immune-precipitation with HDAC1. Furthermore, our ChIP data showed a greater PCR product amplification of proximal Ncx1 promoter, from experimental groups that were subjected to Entinostat (n=3). Our cumulative data suggests that Class I HDAC inhibition stabilizes a repressor complex on the Ncx1 promoter that hinders hypertrophy- mediated Ncx1 upregulation. Class specific HDAC inhibition may be useful in the stabilization and repression of aberrantly expressed genes that contribute to poor clinical outcomes in cardiac hypertrophy.
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abstract 238 class i hdac inhibition prevents ncx1 upregulation by stabilizing an hdac5 hdac1 sin3a repressor complex during cardiac hypertrophy
Circulation Research, 2013Co-Authors: Sabina Wang, Lillianne G Harris, Santhosh K Mani, Donald R MenickAbstract:Cardiac hypertrophy is often associated with the activation of signaling pathways that perpetuate altered calcium efflux and influx. One gene that is upregulated and contributes to altered intracellular calcium concentrations and worsening contractility during cardiac hypertrophy is the Sodium Calcium Exchanger ( Ncx1 ). Molecular studies implicate histone deacetylases (HDACs) in possibly regulating the expression of this gene. Our recent work reveals that HDAC1, HDAC5 and Sin3a interact and are recruited to the Ncx1 promoter through the Nkx2.5 transcription factor. Interestingly, we observed greater associated/interaction of the HDAC1-HDAC5/Sin3a repressor complex upon broad HDAC inhibition. Taken together, we hypothesized that HDAC inhibition, stabilizes an HDAC1-HDAC5/Sin3a repressor complex during cardiac hypertrophy. We addressed this hypothesis by treating isolated adult cardiomyocytes with class specific HDAC inhibitors since HDAC1 is a Class I HDAC and HDAC5 is a Class IIa HDAC. Co-Immunoprecipitation (Co-IP) revealed a greater association of repressor complex molecules in the presence of Entinostat, a Class I HDAC inhibitor compared to both non-treated control and TSA, a broad HDAC inhibitor (n=3). These works show enhanced recruitment Sin3a (co-repressor) at the proximal promoter of NCX1 as demonstrated by Chromatin-Immunoprecipitation (ChIP) (n=3). To test whether these observations translated into in vivo models, we subjected mice to transaortic constriction (TAC) to induce hypertrophy. In this model, Co-IP revealed results that similar to our in vitro studies with greater immuno- detection of repressor complex component, Sin3a after immune-precipitation with HDAC1. Furthermore, our ChIP data showed a greater PCR product amplification of proximal Ncx1 promoter, from experimental groups that were subjected to Entinostat (n=3). Our cumulative data suggests that Class I HDAC inhibition stabilizes a repressor complex on the Ncx1 promoter that hinders hypertrophy- mediated Ncx1 upregulation. Class specific HDAC inhibition may be useful in the stabilization and repression of aberrantly expressed genes that contribute to poor clinical outcomes in cardiac hypertrophy.
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Abstract 236: HDAC5 is Required for Recruitment of an HDAC1/Sin3a Repressor Complex to the Ncx1 Promoter During Cardiac Hypertrophy
Circulation Research, 2013Co-Authors: Lillianne G Harris, Sabina Wang, Santhosh K Mani, Harinath Kasiganesan, Donald R MenickAbstract:Background: Pressure overload can lead to aberrant gene expression and subsequent adverse hypertrophic changes in cardiac tissue. Histone deacetylases (HDACs) play an important role in alteration of gene expression during cardiac hypertrophy. We observed that class I/IIb HDAC inhibitors, TSA and Vorinostat prevent upregulation of the sodium calcium exchanger gene, Ncx1 , in response to cardiac hypertrophy. Chromatin immunoprecipitation (ChIP) demonstrates the class I HDAC, HDAC1, class IIa HDAC, HDAC5 and co-repressor, Sin3a are recruited to the Ncx1 promoter via Nkx2.5. Class IIa HDACs have very poor catalytic activity and can interact with many specific transcription factors. Thus, we hypothesized , that the class IIa, HDAC5 acts as a scaffold to recruit the class I HDAC/Sin3a complex to the Ncx1 promoter. Methods and Results: To test our hypothesis adult cardiomyocytes were treated with either vehicle (control) or class specific HDAC inhibitors: class I (Entinostat), or class IIa (dPAHA). We found that class I HDAC inhibitor, Entinostat, abrogates adrenergic stimulated upregulation of Ncx1 expression in adult cardiomyocytes to almost control levels (p Ncx1 expression (p>0.05 Student’s t; n=4). Also, Entinostat inhibits Ncx1 upregulation in a transaortic constriction (TAC) model of hypertrophy. We assessed the role class IIa HDAC5 in Ncx1 regulation, by subjecting HDAC5-Knockout mice (HDAC5-KO) to TAC. We saw no induction of Ncx1 expression post-TAC (n=5). Furthermore, Co-IP and ChIP analyses show that interactions between the Sin3a/HDAC1 complex and Nkx2.5 are lost in the absence of HDAC5 expression and fail to be recruited to the Ncx1 promoter. To conclude , our data suggests the catalytic activity of HDAC5 is not essential but rather HDAC5 is a scaffold that recruits the class I HDAC1–Sin3a complex to the Ncx1 promoter. Our novel findings provide insight into possible roles of class IIa HDACs in regulation of gene expression and efficacy of HDAC inhibitors to treat cardiac pathologies.
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abstract 236 hdac5 is required for recruitment of an hdac1 sin3a repressor complex to the ncx1 promoter during cardiac hypertrophy
Circulation Research, 2013Co-Authors: Lillianne G Harris, Sabina Wang, Santhosh K Mani, Harinath Kasiganesan, Donald R MenickAbstract:Background: Pressure overload can lead to aberrant gene expression and subsequent adverse hypertrophic changes in cardiac tissue. Histone deacetylases (HDACs) play an important role in alteration of gene expression during cardiac hypertrophy. We observed that class I/IIb HDAC inhibitors, TSA and Vorinostat prevent upregulation of the sodium calcium exchanger gene, Ncx1 , in response to cardiac hypertrophy. Chromatin immunoprecipitation (ChIP) demonstrates the class I HDAC, HDAC1, class IIa HDAC, HDAC5 and co-repressor, Sin3a are recruited to the Ncx1 promoter via Nkx2.5. Class IIa HDACs have very poor catalytic activity and can interact with many specific transcription factors. Thus, we hypothesized , that the class IIa, HDAC5 acts as a scaffold to recruit the class I HDAC/Sin3a complex to the Ncx1 promoter. Methods and Results: To test our hypothesis adult cardiomyocytes were treated with either vehicle (control) or class specific HDAC inhibitors: class I (Entinostat), or class IIa (dPAHA). We found that class I HDAC inhibitor, Entinostat, abrogates adrenergic stimulated upregulation of Ncx1 expression in adult cardiomyocytes to almost control levels (p Ncx1 expression (p>0.05 Student’s t; n=4). Also, Entinostat inhibits Ncx1 upregulation in a transaortic constriction (TAC) model of hypertrophy. We assessed the role class IIa HDAC5 in Ncx1 regulation, by subjecting HDAC5-Knockout mice (HDAC5-KO) to TAC. We saw no induction of Ncx1 expression post-TAC (n=5). Furthermore, Co-IP and ChIP analyses show that interactions between the Sin3a/HDAC1 complex and Nkx2.5 are lost in the absence of HDAC5 expression and fail to be recruited to the Ncx1 promoter. To conclude , our data suggests the catalytic activity of HDAC5 is not essential but rather HDAC5 is a scaffold that recruits the class I HDAC1–Sin3a complex to the Ncx1 promoter. Our novel findings provide insight into possible roles of class IIa HDACs in regulation of gene expression and efficacy of HDAC inhibitors to treat cardiac pathologies.
C Angiolilli - One of the best experts on this subject based on the ideXlab platform.
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histone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast like synoviocytes
Annals of the Rheumatic Diseases, 2017Co-Authors: Pawel A Kabala, Aleksander M. Grabiec, C Angiolilli, Iris M Van Baarsen, Bradley S FergusonAbstract:Objectives Non-selective histone deacetylase (HDAC) inhibitors (HDACi) have demonstrated anti-inflammatory properties in both in vitro and in vivo models of rheumatoid arthritis (RA). Here, we investigated the potential contribution of specific class I and class IIb HDACs to inflammatory gene expression in RA fibroblast-like synoviocytes (FLS). Methods RA FLS were incubated with pan-HDACi (ITF2357, givinostat) or selective HDAC1/2i, HDAC3/6i, HDAC6i and HDAC8i. Alternatively, FLS were transfected with HDAC3, HDAC6 or interferon (IFN)-α/β receptor alpha chain (IFNAR1) siRNA. mRNA expression of interleukin (IL)-1β-inducible genes was measured by quantitative PCR (qPCR) array and signalling pathway activation by immunoblotting and DNA-binding assays. Results HDAC3/6i, but not HDAC1/2i and HDAC8i, significantly suppressed the majority of IL-1β-inducible genes targeted by pan-HDACi in RA FLS. Silencing of HDAC3 expression reproduced the effects of HDAC3/6i on gene regulation, contrary to HDAC6-specific inhibition and HDAC6 silencing. Screening of the candidate signal transducers and activators of transcription (STAT)1 transcription factor revealed that HDAC3/6i abrogated STAT1 Tyr701 phosphorylation and DNA binding, but did not affect STAT1 acetylation. HDAC3 activity was required for type I IFN production and subsequent STAT1 activation in FLS. Suppression of type I IFN release by HDAC3/6i resulted in reduced expression of a subset of IFN-dependent genes, including the chemokines CXCL9 and CXCL11. Conclusions Inhibition of HDAC3 in RA FLS largely recapitulates the effects of pan-HDACi in suppressing inflammatory gene expression, including type I IFN production in RA FLS. Our results identify HDAC3 as a potential therapeutic target in the treatment of RA and type I IFN-driven autoimmune diseases.
Eric N Olson - One of the best experts on this subject based on the ideXlab platform.
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hdac1 and hdac2 act redundantly to control p63 and p53 functions in epidermal progenitor cells
Developmental Cell, 2010Co-Authors: Matthew R Leboeuf, Anne Terrell, Sohum Trivedi, Satrajit Sinha, Jonathan A Epstein, Edward E Morrisey, Eric N Olson, Sarah E MillarAbstract:Epidermal and hair follicle development from surface ectodermal progenitor cells requires coordinated changes in gene expression. Histone deacetylases alter gene expression programs through modification of chromatin and transcription factors. We find that deletion of ectodermal Hdac1 and Hdac2 results in dramatic failure of hair follicle specification and epidermal proliferation and stratification, phenocopying loss of the key ectodermal transcription factor p63. Although expression of p63 and its positively regulated basal cell targets is maintained in Hdac1/2-deficient ectoderm, targets of p63-mediated repression, including p21, 14-3-3σ, and p16/INK4a, are ectopically expressed, and HDACs bind and are active at their promoter regions in normal undifferentiated keratinocytes. Mutant embryos display increased levels of acetylated p53, which opposes p63 functions, and p53 is required for HDAC inhibitor-mediated p21 expression in keratinocytes. Our data identify critical requirements for HDAC1/2 in epidermal development and indicate that HDAC1/2 directly mediate repressive functions of p63 and suppress p53 activity.
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histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development
Molecular and Cellular Biology, 2004Co-Authors: Shurong Chang, Chun Li Zhang, Timothy A Mckinsey, James A Richardson, Joseph A Hill, Eric N OlsonAbstract:The adult heart responds to stress signals by hypertrophic growth, which is often accompanied by activation of a fetal cardiac gene program and eventual cardiac demise. We showed previously that histone deacetylase 9 (HDAC9) acts as a suppressor of cardiac hypertrophy and that mice lacking HDAC9 are sensitized to cardiac stress signals. Here we report that mice lacking HDAC5 display a similar cardiac phenotype and develop profoundly enlarged hearts in response to pressure overload resulting from aortic constriction or constitutive cardiac activation of calcineurin, a transducer of cardiac stress signals. In contrast, mice lacking either HDAC5 or HDAC9 show a hypertrophic response to chronic β-adrenergic stimulation identical to that of wild-type littermates, suggesting that these HDACs modulate a specific subset of cardiac stress response pathways. We also show that compound mutant mice lacking both HDAC5 and HDAC9 show a propensity for lethal ventricular septal defects and thin-walled myocardium. These findings reveal central roles for HDACs 5 and 9 in the suppression of a subset of cardiac stress signals as well as redundant functions in the control of cardiac development.
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activation of the myocyte enhancer factor 2 transcription factor by calcium calmodulin dependent protein kinase stimulated binding of 14 3 3 to histone deacetylase 5
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Timothy A Mckinsey, Chun Li Zhang, Eric N OlsonAbstract:Abstract Skeletal muscle differentiation is controlled by interactions between myocyte enhancer factor-2 (MEF2) and myogenic basic helix—loop–helix transcription factors. Association of MEF2 with histone deacetylases (HDAC) -4 and -5 results in repression of MEF2 target genes and inhibition of myogenesis. Calcium/calmodulin-dependent protein kinase (CaMK) signaling promotes myogenesis by disrupting MEF2–HDAC complexes and stimulating HDAC nuclear export. To further define the mechanisms that confer CaMK responsiveness to HDAC4 and -5, we performed yeast two-hybrid screens to identify HDAC-interacting factors. These screens revealed interactions between HDAC4 and members of the 14-3-3 family of proteins, which function as signal-dependent intracellular chaperones. HDAC4 binds constitutively to 14-3-3 in yeast and mammalian cells, whereas HDAC5 binding to 14-3-3 is largely dependent on CaMK signaling. CaMK phosphorylates serines -259 and -498 in HDAC5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to HDAC5 is required for CaMK-dependent disruption of MEF2–HDAC complexes and nuclear export of HDAC5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.
