scholarly journals Histone deacetylase 2–mediated deacetylation of the glucocorticoid receptor enables NF-κB suppression

2005 ◽  
Vol 203 (1) ◽  
pp. 7-13 ◽  
Author(s):  
Kazuhiro Ito ◽  
Satoshi Yamamura ◽  
Sarah Essilfie-Quaye ◽  
Borja Cosio ◽  
Misako Ito ◽  
...  
Keyword(s):  
Gene Expression ◽  
Glucocorticoid Receptor ◽  
Histone Deacetylase ◽  
Nuclear Translocation ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Site Directed Mutagenesis ◽  
Chronic Obstructive ◽  
Histone Deacetylase Inhibition ◽  
Histone Deacetylase 2

Glucocorticoids are the most effective antiinflammatory agents for the treatment of chronic inflammatory diseases even though some diseases, such as chronic obstructive pulmonary disease (COPD), are relatively glucocorticoid insensitive. However, the molecular mechanism of this glucocorticoid insensitivity remains uncertain. We show that a defect of glucocorticoid receptor (GR) deacetylation caused by impaired histone deacetylase (HDAC) 2 induces glucocorticoid insensitivity toward nuclear factor (NF)-κB–mediated gene expression. Specific knockdown of HDAC2 by RNA interference resulted in reduced sensitivity to dexamethasone suppression of interleukin 1β–induced granulocyte/macrophage colony-stimulating factor production. Loss of HDAC2 did not reduce GR nuclear translocation, GR binding to glucocorticoid response element (GRE) on DNA, or GR-induced DNA or gene induction but inhibited the association between GR and NF-κB. GR becomes acetylated after ligand binding, and HDAC2-mediated GR deacetylation enables GR binding to the NF-κB complex. Site-directed mutagenesis of K494 and K495 reduced GR acetylation, and the ability to repress NF-κB–dependent gene expression becomes insensitive to histone deacetylase inhibition. In conclusion, we show that overexpression of HDAC2 in glucocorticoid-insensitive alveolar macrophages from patients with COPD is able to restore glucocorticoid sensitivity. Thus, reduction of HDAC2 plays a critical role in glucocorticoid insensitivity in repressing NF-κB–mediated, but not GRE-mediated, gene expression.

scholarly journals Genome-Wide STAT3 Binding Analysis after Histone Deacetylase Inhibition Reveals Novel Target Genes in Dendritic Cells

2016 ◽  
Vol 9 (2) ◽  
pp. 126-144 ◽  
Author(s):  
Yaping Sun ◽  
Matthew Iyer ◽  
Richard McEachin ◽  
Meng Zhao ◽  
Yi-Mi Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dendritic Cells ◽  
Histone Deacetylase ◽  
Antigen Processing ◽  
Target Genes ◽  
Hdac Inhibition ◽  
Histone Deacetylase Inhibition ◽  
Immune Effector ◽  
Chip Sequencing ◽  
Genome Wide

STAT3 is a master transcriptional regulator that plays an important role in the induction of both immune activation and immune tolerance in dendritic cells (DCs). The transcriptional targets of STAT3 in promoting DC activation are becoming increasingly understood; however, the mechanisms underpinning its role in causing DC suppression remain largely unknown. To determine the functional gene targets of STAT3, we compared the genome-wide binding of STAT3 using ChIP sequencing coupled with gene expression microarrays to determine STAT3-dependent gene regulation in DCs after histone deacetylase (HDAC) inhibition. HDAC inhibition boosted the ability of STAT3 to bind to distinct DNA targets and regulate gene expression. Among the top 500 STAT3 binding sites, the frequency of canonical motifs was significantly higher than that of noncanonical motifs. Functional analysis revealed that after treatment with an HDAC inhibitor, the upregulated STAT3 target genes were those that were primarily the negative regulators of proinflammatory cytokines and those in the IL-10 signaling pathway. The downregulated STAT3-dependent targets were those involved in immune effector processes and antigen processing/presentation. The expression and functional relevance of these genes were validated. Specifically, functional studies confirmed that the upregulation of IL-10Ra by STAT3 contributed to the suppressive function of DCs following HDAC inhibition.

scholarly journals α-Actinin 4 Links Vasopressin Short-Term and Long-Term Regulation of Aquaporin-2 in Kidney Collecting Duct Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Cheng-Hsuan Ho ◽  
Hsiu-Hui Yang ◽  
Shih-Han Su ◽  
Ai-Hsin Yeh ◽  
Ming-Jiun Yu
Keyword(s):  
Gene Expression ◽  
Glucocorticoid Receptor ◽  
Nuclear Translocation ◽  
Collecting Duct ◽  
Apical Plasma Membrane ◽  
Membrane Insertion ◽  
Short Term ◽  
Aquaporin 2 ◽  
Mrna And Protein Expression

Water permeability of the kidney collecting ducts is regulated by the peptide hormone vasopressin. Between minutes and hours (short-term), vasopressin induces trafficking of the water channel protein aquaporin-2 to the apical plasma membrane of the collecting duct principal cells to increase water permeability. Between hours and days (long-term), vasopressin induces aquaporin-2 gene expression. Here, we investigated the mechanisms that bridge the short-term and long-term vasopressin-mediated aquaporin-2 regulation by α-actinin 4, an F-actin crosslinking protein and a transcription co-activator of the glucocorticoid receptor. Vasopressin induced F-actin depolymerization and α-actinin 4 nuclear translocation in the mpkCCD collecting duct cell model. Co-immunoprecipitation followed by immunoblotting showed increased interaction between α-actinin 4 and glucocorticoid receptor in response to vasopressin. ChIP-PCR showed results consistent with α-actinin 4 and glucocorticoid receptor binding to the aquaporin-2 promoter. α-actinin 4 knockdown reduced vasopressin-induced increases in aquaporin-2 mRNA and protein expression. α-actinin 4 knockdown did not affect vasopressin-induced glucocorticoid receptor nuclear translocation, suggesting independent mechanisms of vasopressin-induced nuclear translocation of α-actinin 4 and glucocorticoid receptor. Glucocorticoid receptor knockdown profoundly reduced vasopressin-induced increases in aquaporin-2 mRNA and protein expression. In the absence of glucocorticoid analog dexamethasone, vasopressin-induced increases in glucocorticoid receptor nuclear translocation and aquaporin-2 mRNA were greatly reduced. α-actinin 4 knockdown further reduced vasopressin-induced increase in aquaporin-2 mRNA in the absence of dexamethasone. We conclude that glucocorticoid receptor plays a major role in vasopressin-induced aquaporin-2 gene expression that can be enhanced by α-actinin 4. In the absence of vasopressin, α-actinin 4 crosslinks F-actin underneath the apical plasma membrane, impeding aquaporin-2 membrane insertion. Vasopressin-induced F-actin depolymerization in one hand facilitates aquaporin-2 apical membrane insertion and in the other hand frees α-actinin 4 to enter the nucleus where it binds glucocorticoid receptor to enhance aquaporin-2 gene expression.

microRNA-223 suppresses histone deacetylase 2 in chronic obstructive pulmonary disease

2015 ◽  
Author(s):  
Caroline Leuenberger ◽  
Claudio Schuoler ◽  
Célia Mignan ◽  
Thomas Rechsteiner ◽  
Malcolm Kohler ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Histone Deacetylase ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Histone Deacetylase 2

Response to histone deacetylase inhibition of novel PML/RARα mutants detected in retinoic acid–resistant APL cells

Blood ◽  
2002 ◽  
Vol 100 (7) ◽  
pp. 2586-2596 ◽  
Author(s):  
Sylvie Côté ◽  
Angelika Rosenauer ◽  
Andrea Bianchini ◽  
Karen Seiter ◽  
Jonathan Vandewiele ◽  
...  
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Cell Line ◽  
Histone Deacetylase ◽  
Fusion Gene ◽  
Combined Treatment ◽  
Resistant Cell Line ◽  
Dominant Negative ◽  
Missense Mutations ◽  
Histone Deacetylase Inhibition

Resistance to all-trans retinoic acid (ATRA) remains a clinical problem in the treatment of acute promyelocytic leukemia (APL) and provides a model for the development of novel therapies. Molecular alterations in the ligand-binding domain (LBD) of the PML/RARα fusion gene that characterizes APL constitute one mechanism of acquired resistance to ATRA. We identified missense mutations in PML/RARα from an additional ATRA-resistant patient at relapse and in a novel ATRA-resistant cell line, NB4-MRA1. These cause altered binding to ligand and transcriptional coregulators, leading to a dominant-negative block of transcription. These mutations are in regions of the LBD that appear to be mutational hot spots occurring repeatedly in ATRA-resistant APL patient cells. We evaluated whether histone deacetylase (HDAC) inhibition could overcome the effects of these mutations on ATRA-induced gene expression. Cotreatment with ATRA and TSA restoredRARβ gene expression in NB4-MRA1 cells, whose PML/RARα mutation is in helix 12 of the LBD, but not in an APL cell line harboring the patient-derived PML/RARα mutation, which was between helix 5 and 6. Furthermore, ATRA combined with TSA increases histone 4 acetylation on the RARβ promoter only in NB4-MRA1 cells. Consistent with these results, the combined treatment induces differentiation of NB4-MRA1 only. Thus, the ability of an HDAC inhibitor to restore ATRA sensitivity in resistant cells may depend on their specific molecular defects. The variety of PML/RARαmutations arising in ATRA-resistant patients begins to explain how APL patients in relapse may differ in response to transcription therapy with HDAC inhibitors.

scholarly journals Epigenetic mechanisms shape the underlining expression regulatory mechanisms of the STAT3 in multiple sclerosis disease

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Arezoo Hosseini ◽  
Zohreh Babaloo ◽  
Tohid Gharibi ◽  
Navid Shomali ◽  
Faroogh Marofi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Diseases ◽  
Mrna Level ◽  
Critical Role ◽  
Methylation Status ◽  
Significant Negative Correlation ◽  
Treg Cells ◽  
Immunological Tolerance ◽  
Dna Hypermethylation ◽  
T Helper 17

Abstract Objectives Immunological tolerance is mediated by CD4+CD25+ regulatory T (Treg) cells. Studies have shown that thymic and peripheral generations of Treg cells depend on the CD28 signaling pathway. T helper 17 (Th17) cells are involved in the pathophysiology of various inflammatory diseases. Cytokines, such as interleukin (IL)-6 and TGF-β, regulate the reciprocal development of Th17 and Treg cells. In CD4+ T cells, signal transducer and activator of transcription 3 (STAT3) play a critical role in the induction of Th17 cell differentiation and inhibition of Treg cell development. Results In this study, we investigated the STAT3 methylation and gene expression status in patients with MS. Our study demonstrated that the level of STAT3 methylation decreased in relapsing–remitting MS patient compared to control groups, which the decreases were statistically significant. STAT3 gene expression increased in patient group relative to healthy one, and the increases were found to be statistically significant. According to our findings, it can be suggested that DNA hypermethylation of STAT3 affects the gene expression. In addition, there is a strong and significant negative correlation between the methylation status and mRNA level of STAT3.

scholarly journals Histone deacetylase inhibition leads to regulatory histone mark alterations and impairs meiosis in oocytes

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Louis Legoff ◽  
Ouzna Dali ◽  
Elena De La Mata Santaella ◽  
Christian Jaulin ◽  
Shereen Cynthia D’Cruz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Histone Deacetylase ◽  
Epigenetic Marks ◽  
Histone Deacetylase Inhibition ◽  
Expression Of Genes ◽  
Germ Cell Specification ◽  
Genes Encoding ◽  
Related Transcription Factor ◽  
Inhibitor Drug

Abstract Background Panobinostat (PB), a histone deacetylase (HDAC) inhibitor drug, is clinically used in the treatment of cancers. We investigated the effects of PB on murine ovarian functions in embryos and adult animals. Methods C57BL/6J mice were treated with 5 mg/kg PB on alternate days from embryonic day (E) 6.5 to E15.5. We analysed the effects of PB on the ovaries by using immunofluorescence, gene expression analysis and DNA methylation analysis techniques. Results At E15.5, we observed increases in histone H3K9Ac, H4Ac and H3K4me3 marks, while the level of the silencing H3K9me3 mark decreased. Synaptonemal complex examination at E15.5, E17.5 and E18.5 showed a delay in meiotic progression characterized by the absence of synaptonemal complexes at E15.5 and the persistence of double-strand breaks (DSBs) at E17.5 and E18.5 in PB-exposed oocytes. We found that exposure to PB led to changes in the expression of 1169 transcripts at E15.5. Genes regulated by the male-specific factors SRY-Box Transcription Factor 9 (SOX9) and Doublesex and Mab-3-related Transcription factor 1 (DMRT1) were among the most upregulated genes in the ovaries of PB-exposed mice. In contrast, PB treatment led to decreases in the expression of genes regulated by the WNT4 pathway. Notably, we observed 119 deregulated genes encoding Zn-finger proteins. The observed alterations in epigenetic marks and gene expression correlated with decreases in the numbers of germ cells at E15.5. After birth, PB-exposed ovaries showed increased proliferation of primary and secondary follicles. We also observed decreases in the numbers of primordial, primary and secondary follicles in adult ovaries from mice that were exposed to PB in utero. Finally, epigenetic alterations such as decreased H3K4me3 and increased H4 acetylation levels were also detected in somatic cells surrounding fully grown oocytes. Conclusion Our data suggest that inhibition of histone deacetylase by PB during a critical developmental window affects reprogramming and germ cell specification via alteration of epigenetic marks.

PECAM-1-dependent heme oxygenase-1 regulation via an Nrf2-mediated pathway in endothelial cells

2014 ◽  
Vol 111 (06) ◽  
pp. 1077-1088 ◽  
Author(s):  
Yarúa Jaimes ◽  
Ananta Paine ◽  
Constanca Figueiredo ◽  
Britta Eiz-Vesper ◽  
Rainer Blasczyk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Heme Oxygenase ◽  
Nuclear Translocation ◽  
Critical Role ◽  
Chinese Hamster ◽  
Human Neutrophils ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Functional Link

SummaryThe antioxidant enzyme heme oxygenase (HO)-1, which catalyses the first and rate-limiting step of heme degradation, has major anti-inflammatory and immunomodulatory effects via its cell-type-specific functions in the endothelium. In the current study, we investigated whether the key endothelial adhesion and signalling receptor PECAM-1 (CD31) might be involved in the regulation of HO-1 gene expression in human endothelial cells (ECs). To this end PECAM-1 expression was down-regulated in human umbilical vein ECs (HUVECs) by an adenoviral vector-based knockdown approach. PECAM-1 knockdown markedly induced HO-1, but not the constitutive HO isoform HO-2. Nuclear translocation of the transcription factor NF-E2-related factor-2 (Nrf2), which is a master regulator of the inducible antioxidant cell response, and intracellular levels of reactive oxygen species (ROS) were increased in PECAM-1-deficient HUVECs, respectively. PECAM-1-dependent HO-1 regulation was also examined in PECAM-1 over-expressing Chinese hamster ovary and murine L-cells. Endogenous HO-1 gene expression and reporter gene activity of transiently transfected luciferase HO-1 promoter constructs with Nrf2 target sequences were decreased in PECAM-1 over-expressing cells. Moreover, a regulatory role of ROS for HO-1 regulation in these cells is demonstrated by studies with the antioxidant N-acetylcysteine and exogenous hydrogenperoxide. Finally, direct interaction of PECAM-1 with a native complex of its binding partner NB1 (CD177) and serine proteinase 3 (PR3) from human neutrophils, markedly induced HO-1 expression in HUVECs. Taken together, we demonstrate a functional link between HO-1 gene expression and PECAM-1 in human ECs, which might play a critical role in the regulation of inflammation.

L1CAM Beneficially Inhibits Histone Deacetylase 2 Expression under Conditions of Alzheimer’s Disease

2020 ◽  
Vol 17 (4) ◽  
pp. 382-392 ◽  
Author(s):  
Chengliang Hu ◽  
Junkai Hu ◽  
Xianghe Meng ◽  
Hongli Zhang ◽  
Huifan Shen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glucocorticoid Receptor ◽  
Histone Deacetylase ◽  
Cortical Neurons ◽  
Hippocampal Neurons ◽  
Extracellular Domain ◽  
Histone Deacetylase 2 ◽  
Protein Levels ◽  
Deficient Mice

Background: Cognitive capacities in Alzheimer’s Disease (AD) are impaired by an epigenetic blockade mediated by histone deacetylase 2 (HDAC2), which prevents the transcription of genes that are important for synaptic plasticity. Objective: Investigation of the functional relationship between cell adhesion molecule L1 and HDAC2 in AD. Methods: Cultures of dissociated cortical and hippocampal neurons from wild-type or L1-deficient mice were treated with Aβ1-42 for 24 h. After removal of Aβ1-42 cells were treated with the recombinant L1 extracellular domain (rL1) for 24 h followed by immunohistochemistry, western blotting, and reverse transcription PCR to evaluate the interaction between L1 and HDAC2. Results: Aβ and HDAC2 protein levels were increased in APPSWE/L1+/- mutant brains compared to APPSWE mutant brains. Administration of the recombinant extracellular domain of L1 to cultured cortical and hippocampal neurons reduced HDAC2 mRNA and protein levels. In parallel, reduced phosphorylation levels of glucocorticoid receptor 1 (GR1), which is implicated in regulating HDAC2 levels, was observed in response to L1 administration. Application of a glucocorticoid receptor inhibitor reduced Aβ-induced GR1 phosphorylation and prevented the increase in HDAC2 levels. HDAC2 protein levels were increased in cultured cortical neurons from L1-deficient mice. This change could be reversed by the administration of the recombinant extracellular domain of L1. Conclusion: Our results suggest that some functionally interdependent activities of L1 and HDAC2 contribute to ameliorating the phenotype of AD by GR1 dephosphorylation, which leads to reduced HDAC2 expression. The combined findings encourage further investigations on the beneficial effects of L1 in the treatment of AD.

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