113 results on '"Seiser C"'
Search Results
2. EVI-1 and MDS1/EVI1: oncogene and anti-oncogene in myeloid leukemia?: 584
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Vinatzer, U., Aytekin, M., Taplick, J., Jäger, U., Gruener, H., Schmidt, H. H., Fonatsch, C., Seiser, C., and Wieser, R.
- Published
- 2002
3. Run-on assays
- Author
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WMULLNER, E, primary, SEISER, C, additional, and AGARCIASANZ, J, additional
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- 1996
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4. FRI0055 Histone deacetylase 1 (HDAC1): a novel therapeutic target in rheumatoid arthritis
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Göschl, L, primary, Bonelli, M, additional, Saferding, V, additional, Preglej, T, additional, Seiser, C, additional, Knapp, S, additional, Backlund, J, additional, Bock, C, additional, Mathias, P, additional, Hirahara, K, additional, Scheinecker, C, additional, Steiner, G, additional, and Ellmeier, W, additional
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- 2017
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5. Histone deacetylase recruitment by RARa fusion proteins in promyelocytic leukemia
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Grignani, Francesco, Matteis, S. DE, Nervi, C, Tomassoni, MARIA LETIZIA, Gelmetti, Vania, Cioce, M, Fanelli, M, Ruthardt, M, Ferrara, Francesca, Zamir, I, Seiser, C, Grignani, Fausto, Lazar, M, Minucci, S, and Pelicci, Pier Giuseppe
- Subjects
Leukemia ,Histone Deacetylase ,PML/RAR ,Epigenetics ,Oncogenes - Published
- 1998
6. Enhanced melt pool stirring in welding with dynamic polarised laser beam
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Gräf, S., primary, Staupendahl, G., additional, Seiser, C., additional, Meyer, B.-J., additional, and Müller, F. A., additional
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- 2010
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7. A viral gene that inactivates histone deacetylase 1 (HDAC1); the role of HDAC1 in cellular proliferation
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Colombo, R., primary, Boggio, R., additional, Dorr, K.Z., additional, Seiser, C., additional, Draetta, G.F., additional, and Chiocca, S., additional
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- 2004
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8. Identification of mouse histone deacetylase 1 as a growth factor-inducible gene
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Bartl, S, primary, Taplick, J, additional, Lagger, G, additional, Khier, H, additional, Kuchler, K, additional, and Seiser, C, additional
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- 1997
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9. Characterization of a second RNA-binding protein in rodents with specificity for iron-responsive elements.
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Henderson, B R, primary, Seiser, C, additional, and Kühn, L C, additional
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- 1993
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10. Interleukin-2-dependent transcriptional and post-transcriptional regulation of transferrin receptor mRNA
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Seiser, C., primary, Teixeira, S., additional, and Kühn, L.C., additional
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- 1993
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11. Feedback control of cellular iron metabolism by a cytoplasmic RNA binding protein.
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Neupert, B., primary, Müllner, E.W., additional, Rothenberger, S., additional, Seiser, C., additional, Thompson, N.A., additional, Emery-Goodman, A., additional, and Kühn, L.C., additional
- Published
- 1991
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12. Characterization of the translation-dependent step during iron-regulated decay of transferrin receptor mRNA.
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Posch, M, Sutterluety, H, Skern, T, and Seiser, C
- Abstract
Iron regulates the stability of the mRNA encoding the transferrin receptor (TfR). When iron is scarce, iron regulatory proteins (IRPs) stabilize TfR mRNA by binding to the 3'-untranslated region. High levels of iron induce degradation of TfR mRNA; the translation inhibitor cycloheximide prevents this. To distinguish between cotranslational mRNA decay and a trans effect of translation inhibitors, we designed a reporter system exploiting the properties of the selectable marker gene thymidine kinase (TK). The 3'-untranslated region of human transferrin receptor, which contains all elements necessary for iron-dependent regulation of mRNA stability, was fused to the TK cDNA. In stably transfected mouse fibroblasts, the expression of the reporter gene was perfectly regulated by iron. Introduction of stop codons in the TK coding sequence or insertion of stable stem-loop structures in the leader sequence did not affect on the iron-dependent regulation of the reporter mRNA. This implies that global translation inhibitors stabilize TfR mRNA in trans. Cycloheximide prevented the destabilization of TfR mRNA only in the presence of active IRPs. Inhibition of IRP inactivation by cycloheximide or by the specific proteasome inhibitor MG132 correlated with the stabilization of TfR mRNA. These observations suggest that inhibition of translation by cycloheximide interferes with the rate-limiting step of iron-induced TfR mRNA decay in a trans-acting mechanism by blocking IRP inactivation.
- Published
- 1999
13. Growth-regulated antisense transcription of the mouse thymidine kinase gene.
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Sutterluety, H, Bartl, S, Doetzlhofer, A, Khier, H, Wintersberger, E, and Seiser, C
- Abstract
The expression of the salvage pathway enzyme thymidine kinase (TK) is very low in resting mammalian cells, but increases dramatically when growth-stimulated cells enter S phase. The 30-fold rise in TK mRNA levels in response to growth factors is due to a well-characterized transcriptional activation and less defined post-transcriptional mechanisms. A minigene containing the murine TK promoter and the TK cDNA showed a 3-fold increase in TK mRNA levels after growth induction in stably transfected mouse TK-deficient L fibroblasts. Introduction of the first three TK introns resulted in a 10-fold regulation of TK expression which was predominantly due to repressed TK mRNA levels in serum-deprived cells. Removal of intron 3 from this construct or replacement of the TK promoter by a constitutive SV40 promoter led to a reduced, but still significant increase in TK mRNA levels during the onset of proliferation. These results indicate that both the TK promoter and specific TK introns contribute independently to the growth-dependent regulation of TK mRNA expression. To examine the regulatory mechanisms in more detail we analyzed TK transcription rates and steady-state levels of nuclear transcripts from an SV40 promoter-driven minigene that contains introns 2 and 3 of the TK gene. Using a set of single-stranded probes we detected TK-specific antisense transcription that was up-regulated in resting cells. Similarly, antisense transcription of the endogenous TK gene in Swiss 3T3 cells rose during serum deprivation while sense transcription was regulated in the opposite way. Luciferase reporter assays revealed the presence of a putative antisense promoter in intron 3 of the murine TK gene. These results suggest a negative role for intron-dependent antisense transcription in the regulation of TK mRNA expression in mouse fibroblasts.
- Published
- 1998
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14. Effect of transcription inhibitors on the iron-dependent degradation of transferrin receptor mRNA.
- Author
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Seiser, C, Posch, M, Thompson, N, and Kühn, L C
- Abstract
Transferrin receptor (TfR) mRNA expression is tightly linked to intracellular iron levels. Upon iron deprivation, the iron regulatory protein (IRP) stabilizes TfR mRNA by binding to stem-loop structures in its 3'-untranslated region, whereas increased iron levels result in inactivation of the mRNA-binding protein and rapid degradation of TfR mRNA. Although IRP and the regulation of its RNA binding activity have been studied intensively, little is known about the mechanism of TfR mRNA degradation. In order to get more information about factors involved in this process we investigated the in vivo IRP-RNA interaction and the effect of transcription inhibitors on the iron-dependent decay of TfR mRNA. Here we demonstrate that part of the active IRP co-localizes with TfR mRNA to the rough endoplasmic reticulum. High intracellular iron levels led to a drastic reduction of this active RNA-bound IRP in vivo, indicating that IRP dissociates prior to TfR mRNA decay. Furthermore, the transcription inhibitor actinomycin D and translation inhibitor cycloheximide suppressed TfR mRNA degradation but did not interfere with the IRP dissociation step. Other inhibitors of RNA polymerase II had no effect on iron-dependent degradation of TfR mRNA. However, high concentrations of alpha-amanitin known to block transcription by RNA polymerase III interfered with mRNA decay suggesting the involvement of polymerase III transcripts in the degradation pathway.
- Published
- 1995
15. Histone H4 acetylation during interleukin-2 stimulation of mouse T cells
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Taplick, J., Kurtev, V., Lagger, G., and Seiser, C.
- Published
- 1998
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16. Crucial function of histone deacetylase 1 for differentiation of teratomas in mice and humans
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Lagger S, Meunier D, Mikula M, Brunmeir R, Schlederer M, Artaker M, Pusch O, Gerda Egger, Hagelkruys A, Mikulits W, Weitzer G, Ew, Muellner, Susani M, Kenner L, and Seiser C
17. Regulation of transferrin receptor mRNA expression. Distinct regulatory features in erythroid cells
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Chan, R. Y., Seiser, C., Schulman, H. M., Kühn, L. C., and Ponka, P.
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hemic and lymphatic diseases - Abstract
In proliferating non-erythroid cells, the expression of transferrin receptors (TfR) is negatively regulated by the amount of intracellular iron. Fe-dependent regulation of TfR occurs post-transcriptionally and is mediated by iron-responsive elements (IRE) located in the 3' untranslated region of the TfR mRNA. IREs are recognized by a specific cytoplasmic binding protein (IRE-BP) that, in the absence of Fe, binds with high affinity to TfR mRNA, preventing its degradation. While TfR numbers are positively correlated with proliferation in non-erythroid cells, in hemoglobin-synthesizing cells, their numbers increase during differentiation and are, therefore, negatively correlated with proliferation. This suggests a distinct regulation of erythroid TfR expression and evidence, as follows, for this was found in the present study. (a) With nuclear run-on assays, our experiments show increased TfR mRNA transcription following induction of erythroid differentiation of murine erythroleukemia (MEL) with Me2SO. (b) Me2SO treatment of MEL cells does not increase IRE-BP activity which is, however, increased in uninduced MEL cells by Fe chelators. (c) Following induction of MEL cells, there is an increase in the stability of TfR mRNA, whose level is only slightly affected by iron excess. (d) Heme-synthesis inhibitors, such as succinylacetone and isonicotinic acid hydrazide, which inhibit numerous aspects of erythroid differentiation, also inhibit TfR mRNA expression in induced MEL cells. However, heme-synthesis inhibition does not lead to a decrease in TfR mRNA levels in uninduced MEL cells. Thus, these studies indicate that TfR gene expression is regulated differently in hemoglobin synthesizing as compared to uninduced MEL cells.
18. GSE1 links the HDAC1/CoREST co-repressor complex to DNA damage.
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Vcelkova T, Reiter W, Zylka M, Hollenstein DM, Schuckert S, Hartl M, and Seiser C
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- Cell Nucleus metabolism, Co-Repressor Proteins metabolism, Deubiquitinating Enzymes genetics, Humans, Animals, Mice, Cell Line, DNA Damage, Histones genetics, Histones metabolism
- Abstract
Post-translational modifications of histones are important regulators of the DNA damage response (DDR). By using affinity purification mass spectrometry (AP-MS) we discovered that genetic suppressor element 1 (GSE1) forms a complex with the HDAC1/CoREST deacetylase/demethylase co-repressor complex. In-depth phosphorylome analysis revealed that loss of GSE1 results in impaired DDR, ATR signalling and γH2AX formation upon DNA damage induction. Altered profiles of ATR target serine-glutamine motifs (SQ) on DDR-related hallmark proteins point to a defect in DNA damage sensing. In addition, GSE1 knock-out cells show hampered DNA damage-induced phosphorylation on SQ motifs of regulators of histone post-translational modifications, suggesting altered histone modification. While loss of GSE1 does not affect the histone deacetylation activity of CoREST, GSE1 appears to be essential for binding of the deubiquitinase USP22 to CoREST and for the deubiquitination of H2B K120 in response to DNA damage. The combination of deacetylase, demethylase, and deubiquitinase activity makes the USP22-GSE1-CoREST subcomplex a multi-enzymatic eraser that seems to play an important role during DDR. Since GSE1 has been previously associated with cancer progression and survival our findings are potentially of high medical relevance., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2023
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19. Development of a Cellular Model Mimicking Specific HDAC Inhibitors.
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Hess L, Moos V, and Seiser C
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- Humans, Histone Deacetylase 1 genetics, Histone Deacetylase 1 metabolism, Histone Deacetylases genetics, Histone Deacetylases metabolism, Repressor Proteins, Histone Deacetylase Inhibitors pharmacology, Neoplasms
- Abstract
Class I histone deacetylases (HDACs) are important regulators of cellular functions in health and disease. HDAC1, HDAC2, HDAC3, and HDAC8 are promising targets for the treatment of cancer, neurological, and immunological disorders. These enzymes have both catalytic and non-catalytic functions in the regulation of gene expression. We here describe the generation of a genetic toolbox by the CRISPR/Cas9 methodology in nearly haploid human tumor cells. This novel model system allows to discriminate between catalytic and structural functions of class I HDAC enzymes and to mimic the treatment with specific HDAC inhibitors., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
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20. A toolbox for class I HDACs reveals isoform specific roles in gene regulation and protein acetylation.
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Hess L, Moos V, Lauber AA, Reiter W, Schuster M, Hartl N, Lackner D, Boenke T, Koren A, Guzzardo PM, Gundacker B, Riegler A, Vician P, Miccolo C, Leiter S, Chandrasekharan MB, Vcelkova T, Tanzer A, Jun JQ, Bradner J, Brosch G, Hartl M, Bock C, Bürckstümmer T, Kubicek S, Chiocca S, Bhaskara S, and Seiser C
- Subjects
- Acetylation, Histone Deacetylase 2 genetics, Histone Deacetylase 2 metabolism, Histone Deacetylases genetics, Histone Deacetylases metabolism, Humans, Protein Isoforms genetics, Protein Isoforms metabolism, Histone Deacetylase 1 genetics, Histone Deacetylase 1 metabolism, Histone Deacetylase Inhibitors pharmacology
- Abstract
The class I histone deacetylases are essential regulators of cell fate decisions in health and disease. While pan- and class-specific HDAC inhibitors are available, these drugs do not allow a comprehensive understanding of individual HDAC function, or the therapeutic potential of isoform-specific targeting. To systematically compare the impact of individual catalytic functions of HDAC1, HDAC2 and HDAC3, we generated human HAP1 cell lines expressing catalytically inactive HDAC enzymes. Using this genetic toolbox we compare the effect of individual HDAC inhibition with the effects of class I specific inhibitors on cell viability, protein acetylation and gene expression. Individual inactivation of HDAC1 or HDAC2 has only mild effects on cell viability, while HDAC3 inactivation or loss results in DNA damage and apoptosis. Inactivation of HDAC1/HDAC2 led to increased acetylation of components of the COREST co-repressor complex, reduced deacetylase activity associated with this complex and derepression of neuronal genes. HDAC3 controls the acetylation of nuclear hormone receptor associated proteins and the expression of nuclear hormone receptor regulated genes. Acetylation of specific histone acetyltransferases and HDACs is sensitive to inactivation of HDAC1/HDAC2. Over a wide range of assays, we determined that in particular HDAC1 or HDAC2 catalytic inactivation mimics class I specific HDAC inhibitors. Importantly, we further demonstrate that catalytic inactivation of HDAC1 or HDAC2 sensitizes cells to specific cancer drugs. In summary, our systematic study revealed isoform-specific roles of HDAC1/2/3 catalytic functions. We suggest that targeted genetic inactivation of particular isoforms effectively mimics pharmacological HDAC inhibition allowing the identification of relevant HDACs as targets for therapeutic intervention., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2022
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21. DNA hypomethylation leads to cGAS-induced autoinflammation in the epidermis.
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Beck MA, Fischer H, Grabner LM, Groffics T, Winter M, Tangermann S, Meischel T, Zaussinger-Haas B, Wagner P, Fischer C, Folie C, Arand J, Schöfer C, Ramsahoye B, Lagger S, Machat G, Eisenwort G, Schneider S, Podhornik A, Kothmayer M, Reichart U, Glösmann M, Tamir I, Mildner M, Sheibani-Tezerji R, Kenner L, Petzelbauer P, Egger G, Sibilia M, Ablasser A, and Seiser C
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Animals, Chromosome Aberrations, Cytosol physiology, DNA (Cytosine-5-)-Methyltransferase 1 genetics, Dermatitis immunology, Dermatitis pathology, Humans, Immunity, Innate genetics, Interferon-Induced Helicase, IFIH1 metabolism, Keratinocytes immunology, Keratinocytes metabolism, Keratinocytes pathology, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Transgenic, Nucleotidyltransferases genetics, DNA Methylation, Dermatitis genetics, Epidermis physiopathology, Nucleotidyltransferases metabolism
- Abstract
DNA methylation is a fundamental epigenetic modification, important across biological processes. The maintenance methyltransferase DNMT1 is essential for lineage differentiation during development, but its functions in tissue homeostasis are incompletely understood. We show that epidermis-specific DNMT1 deletion severely disrupts epidermal structure and homeostasis, initiating a massive innate immune response and infiltration of immune cells. Mechanistically, DNA hypomethylation in keratinocytes triggered transposon derepression, mitotic defects, and formation of micronuclei. DNA release into the cytosol of DNMT1-deficient keratinocytes activated signaling through cGAS and STING, thus triggering inflammation. Our findings show that disruption of a key epigenetic mark directly impacts immune and tissue homeostasis, and potentially impacts our understanding of autoinflammatory diseases and cancer immunotherapy., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2021
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22. Histone deacetylase 1 controls CD4 + T cell trafficking in autoinflammatory diseases.
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Hamminger P, Marchetti L, Preglej T, Platzer R, Zhu C, Kamnev A, Rica R, Stolz V, Sandner L, Alteneder M, Kaba E, Waltenberger D, Huppa JB, Trauner M, Bock C, Lyck R, Bauer J, Dupré L, Seiser C, Boucheron N, Engelhardt B, and Ellmeier W
- Subjects
- Animals, Biomarkers, Cell Adhesion, Chemotaxis, Leukocyte genetics, Disease Models, Animal, Disease Susceptibility, Encephalomyelitis, Autoimmune, Experimental diagnosis, Encephalomyelitis, Autoimmune, Experimental etiology, Encephalomyelitis, Autoimmune, Experimental metabolism, Endothelial Cells, Gene Expression Profiling, Gene Expression Regulation, Histone Deacetylase 1 genetics, Immunohistochemistry, Inflammation diagnosis, Intestinal Mucosa immunology, Intestinal Mucosa metabolism, Intestinal Mucosa pathology, Lymphocyte Activation genetics, Lymphocyte Activation immunology, Mice, Mice, Knockout, Autoimmunity, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Chemotaxis, Leukocyte immunology, Histone Deacetylase 1 metabolism, Inflammation etiology, Inflammation metabolism
- Abstract
CD4
+ T cell trafficking is a fundamental property of adaptive immunity. In this study, we uncover a novel role for histone deacetylase 1 (HDAC1) in controlling effector CD4+ T cell migration, thereby providing mechanistic insight into why a T cell-specific deletion of HDAC1 protects against experimental autoimmune encephalomyelitis (EAE). HDAC1-deficient CD4+ T cells downregulated genes associated with leukocyte extravasation. In vitro, HDAC1-deficient CD4+ T cells displayed aberrant morphology and migration on surfaces coated with integrin LFA-1 ligand ICAM-1 and showed an impaired ability to arrest on and to migrate across a monolayer of primary mouse brain microvascular endothelial cells under physiological flow. Moreover, HDAC1 deficiency reduced homing of CD4+ T cells into the intestinal epithelium and lamina propria preventing weight-loss, crypt damage and intestinal inflammation in adoptive CD4+ T cell transfer colitis. This correlated with reduced expression levels of LFA-1 integrin chains CD11a and CD18 as well as of selectin ligands CD43, CD44 and CD162 on transferred circulating HDAC1-deficient CD4+ T cells. Our data reveal that HDAC1 controls T cell-mediated autoimmunity via the regulation of CD4+ T cell trafficking into the CNS and intestinal tissues., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2021
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23. Requirement of DNMT1 to orchestrate epigenomic reprogramming for NPM-ALK-driven lymphomagenesis.
- Author
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Redl E, Sheibani-Tezerji R, Cardona CJ, Hamminger P, Timelthaler G, Hassler MR, Zrimšek M, Lagger S, Dillinger T, Hofbauer L, Draganić K, Tiefenbacher A, Kothmayer M, Dietz CH, Ramsahoye BH, Kenner L, Bock C, Seiser C, Ellmeier W, Schweikert G, and Egger G
- Subjects
- Animals, Biomarkers, Tumor, Computational Biology methods, DNA (Cytosine-5-)-Methyltransferase 1 genetics, DNA Methylation, Disease Models, Animal, Disease Susceptibility, Epigenomics, Gene Deletion, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Humans, Immunohistochemistry, Immunophenotyping, Lymphoma drug therapy, Lymphoma pathology, Mice, Mice, Knockout, Mice, Transgenic, Protein-Tyrosine Kinases metabolism, STAT3 Transcription Factor metabolism, Signal Transduction, Xenograft Model Antitumor Assays, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, DNA (Cytosine-5-)-Methyltransferase 1 metabolism, Epigenesis, Genetic, Lymphoma etiology, Lymphoma metabolism, Protein-Tyrosine Kinases genetics
- Abstract
Malignant transformation depends on genetic and epigenetic events that result in a burst of deregulated gene expression and chromatin changes. To dissect the sequence of events in this process, we used a T-cell-specific lymphoma model based on the human oncogenic nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) translocation. We find that transformation of T cells shifts thymic cell populations to an undifferentiated immunophenotype, which occurs only after a period of latency, accompanied by induction of the MYC-NOTCH1 axis and deregulation of key epigenetic enzymes. We discover aberrant DNA methylation patterns, overlapping with regulatory regions, plus a high degree of epigenetic heterogeneity between individual tumors. In addition, ALK-positive tumors show a loss of associated methylation patterns of neighboring CpG sites. Notably, deletion of the maintenance DNA methyltransferase DNMT1 completely abrogates lymphomagenesis in this model, despite oncogenic signaling through NPM-ALK, suggesting that faithful maintenance of tumor-specific methylation through DNMT1 is essential for sustained proliferation and tumorigenesis., (© 2020 Redl et al.)
- Published
- 2020
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24. Targeting foam cell formation in inflammatory brain diseases by the histone modifier MS-275.
- Author
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Zierfuss B, Weinhofer I, Buda A, Popitsch N, Hess L, Moos V, Hametner S, Kemp S, Köhler W, Forss-Petter S, Seiser C, and Berger J
- Subjects
- Acute Disease, Adult, Autopsy, Gene Expression Profiling, Humans, Immunohistochemistry, Middle Aged, Sequence Analysis, RNA, Young Adult, Adrenoleukodystrophy drug therapy, Adrenoleukodystrophy immunology, Adrenoleukodystrophy metabolism, Benzamides pharmacology, Foam Cells drug effects, Histone Deacetylase Inhibitors pharmacology, Inflammation drug therapy, Inflammation immunology, Inflammation metabolism, Multiple Sclerosis drug therapy, Multiple Sclerosis immunology, Multiple Sclerosis metabolism, Pyridines pharmacology
- Abstract
Objective: To assess class I-histone deacetylase (HDAC) inhibition on formation of lipid-accumulating, disease-promoting phagocytes upon myelin load in vitro, relevant for neuroinflammatory disorders like multiple sclerosis (MS) and cerebral X-linked adrenoleukodystrophy (X-ALD)., Methods: Immunohistochemistry on postmortem brain tissue of acute MS (n = 6) and cerebral ALD (n = 4) cases to analyze activation and foam cell state of phagocytes. RNA-Seq of in vitro differentiated healthy macrophages (n = 8) after sustained myelin-loading to assess the metabolic shift associated with foam cell formation. RNA-Seq analysis of genes linked to lipid degradation and export in MS-275-treated human HAP1 cells and RT-qPCR analysis of HAP1 cells knocked out for individual members of class I HDACs or the corresponding enzymatically inactive knock-in mutants. Investigation of intracellular lipid/myelin content after MS-275 treatment of myelin-laden human foam cells. Analysis of disease characteristic very long-chain fatty acid (VLCFA) metabolism and inflammatory state in MS-275-treated X-ALD macrophages., Results: Enlarged foam cells coincided with a pro-inflammatory, lesion-promoting phenotype in postmortem tissue of MS and cerebral ALD patients. Healthy in vitro myelin laden foam cells upregulated genes linked to LXRα/PPARγ pathways and mimicked a program associated with tissue repair. Treating these cells with MS-275, amplified this gene transcription program and significantly reduced lipid and cholesterol accumulation and, thus, foam cell formation. In macrophages derived from X-ALD patients, MS-275 improved the disease-associated alterations of VLCFA metabolism and reduced the pro-inflammatory status of these cells., Interpretation: These findings identify class I-HDAC inhibition as a potential novel strategy to prevent disease promoting foam cell formation in CNS inflammation., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
- Published
- 2020
- Full Text
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25. Vorinostat in the acute neuroinflammatory form of X-linked adrenoleukodystrophy.
- Author
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Zierfuss B, Weinhofer I, Kühl JS, Köhler W, Bley A, Zauner K, Binder J, Martinović K, Seiser C, Hertzberg C, Kemp S, Egger G, Leitner G, Bauer J, Wiesinger C, Kunze M, Forss-Petter S, and Berger J
- Subjects
- Acute Disease, Adrenoleukodystrophy cerebrospinal fluid, Adrenoleukodystrophy diagnostic imaging, Coenzyme A Ligases drug effects, Humans, Magnetic Resonance Imaging, Outcome Assessment, Health Care, Peroxisomes, ATP Binding Cassette Transporter, Subfamily D drug effects, ATP Binding Cassette Transporter, Subfamily D, Member 1 deficiency, Adrenoleukodystrophy drug therapy, Histone Deacetylase Inhibitors pharmacology, Inflammation drug therapy, Macrophages drug effects, Vorinostat pharmacology
- Abstract
Objective: To identify a pharmacological compound targeting macrophages, the most affected immune cells in inflammatory X-linked adrenoleukodystrophy (cerebral X-ALD) caused by ABCD1 mutations and involved in the success of hematopoietic stem cell transplantation and gene therapy., Methods: A comparative database analysis elucidated the epigenetic repressing mechanism of the related ABCD2 gene in macrophages and identified the histone deacetylase (HDAC) inhibitor Vorinostat as a compound to induce ABCD2 in these cells to compensate for ABCD1 deficiency. In these cells, we investigated ABCD2 and pro-inflammatory gene expression, restoration of defective peroxisomal β-oxidation activity, accumulation of very long-chain fatty acids (VLCFAs) and their differentiation status. We investigated ABCD2 and pro-inflammatory gene expression, restoration of defective peroxisomal ß-oxidation activity, accumulation of very long-chain fatty acids (VLCFA) and differentiation status. Three advanced cerebral X-ALD patients received Vorinostat and CSF and MRI diagnostics was carried out in one patient after 80 days of treatment., Results: Vorinostat improved the metabolic defects in X-ALD macrophages by stimulating ABCD2 expression, peroxisomal ß-oxidation, and ameliorating VLCFA accumulation. Vorinostat interfered with pro-inflammatory skewing of X-ALD macrophages by correcting IL12B expression and further reducing monocyte differentiation. Vorinostat normalized the albumin and immunoglobulin CSF-serum ratios, but not gadolinium enhancement upon 80 days of treatment., Interpretation: The beneficial effects of HDAC inhibitors on macrophages in X-ALD and the improvement of the blood-CSF/blood-brain barrier are encouraging for future investigations. In contrast with Vorinostat, less toxic macrophage-specific HDAC inhibitors might improve also the clinical state of X-ALD patients with advanced inflammatory demyelination., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)
- Published
- 2020
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26. Histone deacetylase 1 (HDAC1): A key player of T cell-mediated arthritis.
- Author
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Göschl L, Preglej T, Boucheron N, Saferding V, Müller L, Platzer A, Hirahara K, Shih HY, Backlund J, Matthias P, Niederreiter B, Hladik A, Kugler M, Gualdoni GA, Scheinecker C, Knapp S, Seiser C, Holmdahl R, Tillmann K, Plasenzotti R, Podesser B, Aletaha D, Smolen JS, Karonitsch T, Steiner G, Ellmeier W, and Bonelli M
- Subjects
- Animals, Arthritis, Rheumatoid pathology, Biomarkers, Collagen adverse effects, Cytokines metabolism, Disease Models, Animal, Gene Expression Regulation, Histone Deacetylase 1 genetics, Humans, Inflammation Mediators metabolism, Mice, Mice, Knockout, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Arthritis, Rheumatoid etiology, Arthritis, Rheumatoid metabolism, Disease Susceptibility, Histone Deacetylase 1 metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism
- Abstract
Rheumatoid Arthritis (RA) represents a chronic T cell-mediated inflammatory autoimmune disease. Studies have shown that epigenetic mechanisms contribute to the pathogenesis of RA. Histone deacetylases (HDACs) represent one important group of epigenetic regulators. However, the role of individual HDAC members for the pathogenesis of arthritis is still unknown. In this study we demonstrate that mice with a T cell-specific deletion of HDAC1 (HDAC1-cKO) are resistant to the development of Collagen-induced arthritis (CIA), whereas the antibody response to collagen type II was undisturbed, indicating an unaltered T cell-mediated B cell activation. The inflammatory cytokines IL-17 and IL-6 were significantly decreased in sera of HDAC1-cKO mice. IL-6 treated HDAC1-deficient CD4
+ T cells showed an impaired upregulation of CCR6. Selective inhibition of class I HDACs with the HDAC inhibitor MS-275 under Th17-skewing conditions inhibited the upregulation of chemokine receptor 6 (CCR6) in mouse and human CD4+ T cells. Accordingly, analysis of human RNA-sequencing (RNA-seq) data and histological analysis of synovial tissue samples from human RA patients revealed the existence of CD4+ CCR6+ cells with enhanced HDAC1 expression. Our data indicate a key role for HDAC1 for the pathogenesis of CIA and suggest that HDAC1 and other class I HDACs might be promising targets of selective HDAC inhibitors (HDACi) for the treatment of RA., Competing Interests: Declaration of competing interest None. This research has received support from the Innovative Medicines Initiative (IMI) Joint Undertaking under grant agreement n°115142 (BTCure), and grant agreement n(o)777357 (RTCure) resources of which are composed of financial contribution from the European Union's Framework Programmes and EFPIA companies' in kind contribution. The work has been supported by the Austrian Science Fund (FWF) project F26193 (to WE) and the FWF special research program SFB F70 (subproject F7003 to MB, F7004 to NB and F7005 to WE)., (Copyright © 2019. Published by Elsevier Ltd.)- Published
- 2020
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27. Histone deacetylases 1 and 2 restrain CD4+ cytotoxic T lymphocyte differentiation.
- Author
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Preglej T, Hamminger P, Luu M, Bulat T, Andersen L, Göschl L, Stolz V, Rica R, Sandner L, Waltenberger D, Tschismarov R, Faux T, Boenke T, Laiho A, Elo LL, Sakaguchi S, Steiner G, Decker T, Bohle B, Visekruna A, Bock C, Strobl B, Seiser C, Boucheron N, and Ellmeier W
- Subjects
- Animals, CD4-Positive T-Lymphocytes drug effects, Fatty Acids pharmacology, Histone Deacetylase 1 genetics, Histone Deacetylase 2 genetics, Humans, Mice, Mice, Knockout, Signal Transduction physiology, T-Lymphocytes, Cytotoxic drug effects, Up-Regulation drug effects, Up-Regulation physiology, CD4-Positive T-Lymphocytes cytology, Cell Differentiation physiology, Histone Deacetylase 1 physiology, Histone Deacetylase 2 physiology, T-Lymphocytes, Cytotoxic physiology
- Abstract
Some effector CD4+ T cell subsets display cytotoxic activity, thus breaking the functional dichotomy of CD4+ helper and CD8+ cytotoxic T lymphocytes. However, molecular mechanisms regulating CD4+ cytotoxic T lymphocyte (CD4+ CTL) differentiation are poorly understood. Here we show that levels of histone deacetylases 1 and 2 (HDAC1-HDAC2) are key determinants of CD4+ CTL differentiation. Deletions of both Hdac1 and 1 Hdac2 alleles (HDAC1cKO-HDAC2HET) in CD4+ T cells induced a T helper cytotoxic program that was controlled by IFN-γ-JAK1/2-STAT1 signaling. In vitro, activated HDAC1cKO-HDAC2HET CD4+ T cells acquired cytolytic activity and displayed enrichment of gene signatures characteristic of effector CD8+ T cells and human CD4+ CTLs. In vivo, murine cytomegalovirus-infected HDAC1cKO-HDAC2HET mice displayed a stronger induction of CD4+ CTL features compared with infected WT mice. Finally, murine and human CD4+ T cells treated with short-chain fatty acids, which are commensal-produced metabolites acting as HDAC inhibitors, upregulated CTL genes. Our data demonstrate that HDAC1-HDAC2 restrain CD4+ CTL differentiation. Thus, HDAC1-HDAC2 might be targets for the therapeutic induction of CD4+ CTLs.
- Published
- 2020
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28. Author Correction: Histone deacetylase function in CD4 + T cells.
- Author
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Ellmeier W and Seiser C
- Abstract
In Table 1 in the originally published version of this article, the phenotype of Hdac1-cKO CD8+ T cells (3rd row) was incorrectly described. This has been corrected in the HTML and PDF versions of the manuscript.
- Published
- 2019
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29. HDAC1 and HDAC2 Regulate Intermediate Progenitor Positioning to Safeguard Neocortical Development.
- Author
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Tang T, Zhang Y, Wang Y, Cai Z, Lu Z, Li L, Huang R, Hagelkruys A, Matthias P, Zhang H, Seiser C, and Xie Y
- Subjects
- Animals, Basic Helix-Loop-Helix Transcription Factors metabolism, Cell Movement genetics, Histone Deacetylase 1 metabolism, Histone Deacetylase 2 metabolism, Malformations of Cortical Development embryology, Mice, Nerve Tissue Proteins metabolism, Neurogenesis, Ependymoglial Cells metabolism, Histone Deacetylase 1 genetics, Histone Deacetylase 2 genetics, Lateral Ventricles embryology, Malformations of Cortical Development genetics, Neocortex embryology, Neural Stem Cells metabolism
- Abstract
Neural progenitors with distinct potential to generate progeny are associated with a spatially distinct microenvironment. Neocortical intermediate progenitors (IPs) in the subventricular zone (SVZ) of the developing brain generate neurons for all cortical layers and are essential for cortical expansion. Here, we show that spatial control of IP positioning is essential for neocortical development. We demonstrate that HDAC1 and HDAC2 regulate the spatial positioning of IPs to form the SVZ. Developmental stage-specific depletion of both HDAC1 and HDAC2 in radial glial progenitors results in mispositioning of IPs at the ventricular surface, where they divide and differentiate into neurons, thereby leading to the cortical malformation. We further identified the proneural gene Neurogenin2 as a key target of HDAC1 and HDAC2 for regulating IP positioning. Our results demonstrate the importance of the spatial positioning of neural progenitors in cortical development and reveal a mechanism underlying the establishment of the SVZ microenvironment., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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30. Histone deacetylase function in CD4 + T cells.
- Author
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Ellmeier W and Seiser C
- Subjects
- Acetylation, Animals, Chromatin metabolism, Gene Expression Regulation genetics, Histones metabolism, Humans, Lymphocyte Activation, Mice, T-Lymphocytes, Helper-Inducer cytology, Histone Acetyltransferases metabolism, Histone Code genetics, Histone Deacetylases metabolism, T-Lymphocytes, Helper-Inducer immunology, T-Lymphocytes, Helper-Inducer metabolism
- Abstract
The differentiation of T helper cell subsets and their acquisition of effector functions are accompanied by changes in gene expression programmes, which in part are regulated and maintained by epigenetic processes. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are key epigenetic regulators that function by mediating dynamic changes in the acetylation of histones at lysine residues. In addition, many non-histone proteins are also acetylated, and reversible acetylation affects their functional properties, demonstrating that HDACs mediate effects beyond the epigenetic regulation of gene expression. In this Review, we discuss studies revealing that HDACs are key regulators of CD4
+ T cell-mediated immunity in mice and humans and that HDACs are promising targets in T cell-mediated immune diseases. Finally, we discuss unanswered questions and future research directions to promote the concept that isoform-selective HDAC inhibitors might broaden the clinical application of HDAC inhibitors beyond their current use in certain types of cancer.- Published
- 2018
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31. Histone deacetylase 1 expression is inversely correlated with age in the short-lived fish Nothobranchius furzeri.
- Author
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Zupkovitz G, Lagger S, Martin D, Steiner M, Hagelkruys A, Seiser C, Schöfer C, and Pusch O
- Subjects
- Animals, Gene Expression Profiling, Histone Deacetylase 1 metabolism, Immunohistochemistry, Mice, Mice, Inbred C57BL, Survival Analysis, Aging, Fishes, Histone Deacetylase 1 genetics
- Abstract
Aging is associated with profound changes in the epigenome, resulting in alterations of gene expression, epigenetic landscape, and genome architecture. Class I Histone deacetylases (HDACs), consisting of HDAC1, HDAC2, HDAC3, and HDAC8, play a major role in epigenetic regulation of chromatin structure and transcriptional control, and have been implicated as key players in the pathogenesis of age-dependent diseases and disorders affecting health and longevity. Here, we report the identification of class I Hdac orthologs and their detailed spatio-temporal expression profile in the short-lived fish Nothobranchius furzeri from the onset of embryogenesis until old age covering the entire lifespan of the organism. Database search of the recently annotated N. furzeri genomes retrieved four distinct genes: two copies of hdac1 and one copy of each hdac3 and hdac8. However, no hdac2 ortholog could be identified. Phylogenetic analysis grouped the individual killifish class I Hdacs within the well-defined terminal clades. We find that upon aging, Hdac1 is significantly down-regulated in muscle, liver, and brain, and this age-dependent down-regulation in brain clearly correlates with increased mRNA levels of the cyclin-dependent kinase inhibitor cdkn1a (p21). Furthermore, this apparent reduction of class I HDACs in transcript and protein levels is mirrored in the mouse brain, highlighting an evolutionarily conserved role of class I HDACs during normal development and in the aging process.
- Published
- 2018
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- View/download PDF
32. A T cell-specific deletion of HDAC1 protects against experimental autoimmune encephalomyelitis.
- Author
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Göschl L, Preglej T, Hamminger P, Bonelli M, Andersen L, Boucheron N, Gülich AF, Müller L, Saferding V, Mufazalov IA, Hirahara K, Seiser C, Matthias P, Penz T, Schuster M, Bock C, Waisman A, Steiner G, and Ellmeier W
- Subjects
- Animals, Cell Movement, Cells, Cultured, Chimera, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental immunology, Histone Deacetylase 1 genetics, Humans, Mice, Mice, Knockout, Multiple Sclerosis immunology, Receptors, CCR4 metabolism, Receptors, CCR6 metabolism, STAT1 Transcription Factor genetics, Encephalomyelitis, Autoimmune, Experimental metabolism, Histone Deacetylase 1 metabolism, Multiple Sclerosis metabolism, STAT1 Transcription Factor metabolism, Th17 Cells physiology
- Abstract
Multiple sclerosis (MS) is a human neurodegenerative disease characterized by the invasion of autoreactive T cells from the periphery into the CNS. Application of pan-histone deacetylase inhibitors (HDACi) ameliorates experimental autoimmune encephalomyelitis (EAE), an animal model for MS, suggesting that HDACi might be a potential therapeutic strategy for MS. However, the function of individual HDAC members in the pathogenesis of EAE is not known. In this study we report that mice with a T cell-specific deletion of HDAC1 (using the Cd4-Cre deleter strain; HDAC1-cKO) were completely resistant to EAE despite the ability of HDAC1cKO CD4
+ T cells to differentiate into Th17 cells. RNA sequencing revealed STAT1 as a prominent upstream regulator of differentially expressed genes in activated HDAC1-cKO CD4+ T cells and this was accompanied by a strong increase in phosphorylated STAT1 (pSTAT1). This suggests that HDAC1 controls STAT1 activity in activated CD4+ T cells. Increased pSTAT1 levels correlated with a reduced expression of the chemokine receptors Ccr4 and Ccr6, which are important for the migration of T cells into the CNS. Finally, EAE susceptibility was restored in WT:HDAC1-cKO mixed BM chimeric mice, indicating a cell-autonomous defect. Our data demonstrate a novel pathophysiological role for HDAC1 in EAE and provide evidence that selective inhibition of HDAC1 might be a promising strategy for the treatment of MS., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2018
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33. HDAC1 and HDAC3 underlie dynamic H3K9 acetylation during embryonic neurogenesis and in schizophrenia-like animals.
- Author
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Večeřa J, Bártová E, Krejčí J, Legartová S, Komůrková D, Rudá-Kučerová J, Štark T, Dražanová E, Kašpárek T, Šulcová A, Dekker FJ, Szymanski W, Seiser C, Weitzer G, Mechoulam R, Micale V, and Kozubek S
- Subjects
- Acetylation, Animals, Antipsychotic Agents pharmacology, Brain drug effects, Brain embryology, Brain pathology, Cannabinoid Receptor Antagonists pharmacology, Disease Models, Animal, Epigenesis, Genetic, Gene Expression Regulation, Developmental, Gestational Age, Histone Deacetylase 1 antagonists & inhibitors, Histone Deacetylase 1 genetics, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases genetics, Methylazoxymethanol Acetate, Mice, Inbred C57BL, Neural Cell Adhesion Molecules genetics, Neural Cell Adhesion Molecules metabolism, Neurons drug effects, Neurons pathology, Protein Processing, Post-Translational, Rats, Sprague-Dawley, Receptor, Cannabinoid, CB1 antagonists & inhibitors, Receptor, Cannabinoid, CB1 metabolism, SOXB1 Transcription Factors genetics, SOXB1 Transcription Factors metabolism, Schizophrenia chemically induced, Schizophrenia drug therapy, Schizophrenia genetics, Signal Transduction, Time Factors, Brain enzymology, Histone Deacetylase 1 metabolism, Histone Deacetylases metabolism, Histones metabolism, Neurogenesis drug effects, Neurons enzymology, Schizophrenia enzymology
- Abstract
Although histone acetylation is one of the most widely studied epigenetic modifications, there is still a lack of information regarding how the acetylome is regulated during brain development and pathophysiological processes. We demonstrate that the embryonic brain (E15) is characterized by an increase in H3K9 acetylation as well as decreases in the levels of HDAC1 and HDAC3. Moreover, experimental induction of H3K9 hyperacetylation led to the overexpression of NCAM in the embryonic cortex and depletion of Sox2 in the subventricular ependyma, which mimicked the differentiation processes. Inducing differentiation in HDAC1-deficient mouse ESCs resulted in early H3K9 deacetylation, Sox2 downregulation, and enhanced astrogliogenesis, whereas neuro-differentiation was almost suppressed. Neuro-differentiation of (wt) ESCs was characterized by H3K9 hyperacetylation that was associated with HDAC1 and HDAC3 depletion. Conversely, the hippocampi of schizophrenia-like animals showed H3K9 deacetylation that was regulated by an increase in both HDAC1 and HDAC3. The hippocampi of schizophrenia-like brains that were treated with the cannabinoid receptor-1 inverse antagonist AM251 expressed H3K9ac at the level observed in normal brains. Together, the results indicate that co-regulation of H3K9ac by HDAC1 and HDAC3 is important to both embryonic brain development and neuro-differentiation as well as the pathophysiology of a schizophrenia-like phenotype., (© 2017 Wiley Periodicals, Inc.)
- Published
- 2018
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34. Generation of Tissue-Specific Mouse Models to Analyze HDAC Functions.
- Author
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Hagelkruys A, Moser MA, and Seiser C
- Subjects
- Animals, Blastocyst cytology, Blotting, Southern, CRISPR-Cas Systems, Chromatin chemistry, Chromosomes, Artificial, Bacterial chemistry, Chromosomes, Artificial, Bacterial metabolism, Crosses, Genetic, Female, Gene Knock-In Techniques, Genetic Vectors chemistry, Histone Deacetylase 1 deficiency, Homologous Recombination, Integrases genetics, Integrases metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mouse Embryonic Stem Cells cytology, Organ Specificity, RNA, Guide, CRISPR-Cas Systems, Blastocyst enzymology, Chromatin metabolism, Epigenesis, Genetic, Genetic Vectors metabolism, Histone Deacetylase 1 genetics, Mouse Embryonic Stem Cells enzymology
- Abstract
Histone deacetylases (HDACs) play crucial roles during mammalian development and for cellular homeostasis. In addition, these enzymes are promising targets for small molecule inhibitors in the treatment of cancer and neurological diseases. Conditional HDAC knock-out mice are excellent tools for defining the functions of individual HDACs in vivo and for identifying the molecular targets of HDAC inhibitors in disease. Here, we describe the generation of tissue-specific HDAC knock-out mice and delineate a strategy for the generation of conditional HDAC knock-in mice.
- Published
- 2017
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35. Dynamic phosphorylation of Histone Deacetylase 1 by Aurora kinases during mitosis regulates zebrafish embryos development.
- Author
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Loponte S, Segré CV, Senese S, Miccolo C, Santaguida S, Deflorian G, Citro S, Mattoscio D, Pisati F, Moser MA, Visintin R, Seiser C, and Chiocca S
- Subjects
- Acetylation, Animals, Genes, Regulator, Histones metabolism, Phosphorylation, Aurora Kinases metabolism, Embryonic Development, Histone Deacetylase 1 metabolism, Mitosis, Zebrafish embryology
- Abstract
Histone deacetylases (HDACs) catalyze the removal of acetyl molecules from histone and non-histone substrates playing important roles in chromatin remodeling and control of gene expression. Class I HDAC1 is a critical regulator of cell cycle progression, cellular proliferation and differentiation during development; it is also regulated by many post-translational modifications (PTMs). Herein we characterize a new mitosis-specific phosphorylation of HDAC1 driven by Aurora kinases A and B. We show that this phosphorylation affects HDAC1 enzymatic activity and it is critical for the maintenance of a proper proliferative and developmental plan in a complex organism. Notably, we find that Aurora-dependent phosphorylation of HDAC1 regulates histone acetylation by modulating the expression of genes directly involved in the developing zebrafish central nervous system. Our data represent a step towards the comprehension of HDAC1 regulation by its PTM code, with important implications in unravelling its roles both in physiology and pathology.
- Published
- 2016
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36. A monoclonal antibody specific for prophase phosphorylation of histone deacetylase 1: a readout for early mitotic cells.
- Author
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Segré CV, Senese S, Loponte S, Santaguida S, Soffientini P, Grigorean G, Cinquanta M, Ossolengo G, Seiser C, and Chiocca S
- Subjects
- Animals, Humans, Mice, Phosphorylation, Antibodies, Monoclonal, Murine-Derived chemistry, Histone Deacetylase 1 chemistry, Histone Deacetylase 1 metabolism, Phosphoproteins chemistry, Phosphoproteins metabolism, Prophase
- Abstract
Histone deacetylases (HDACs) are modification enzymes that regulate a plethora of biological processes. HDAC1, a crucial epigenetic modifier, is deregulated in cancer and subjected to a variety of post-translational modifications. Here, we describe the generation of a new monoclonal antibody that specifically recognizes a novel highly dynamic prophase phosphorylation of serine 406-HDAC1, providing a powerful tool for detecting early mitotic cells.
- Published
- 2016
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37. Essential Nonredundant Function of the Catalytic Activity of Histone Deacetylase 2 in Mouse Development.
- Author
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Hagelkruys A, Mattes K, Moos V, Rennmayr M, Ringbauer M, Sawicka A, and Seiser C
- Subjects
- Animals, Female, Gene Deletion, Gene Expression, Gene Knock-In Techniques, Histone Deacetylase 1 genetics, Histone Deacetylase 1 metabolism, Male, Mice genetics, Mice metabolism, Mice, Inbred C57BL, Mutagenesis, Site-Directed, Phenotype, Point Mutation, Transcriptional Activation, Histone Deacetylase 2 genetics, Histone Deacetylase 2 metabolism, Mice growth & development
- Abstract
The class I histone deacetylases (HDACs) HDAC1 and HDAC2 play partially redundant roles in the regulation of gene expression and mouse development. As part of multisubunit corepressor complexes, these two deacetylases exhibit both enzymatic and nonenzymatic functions. To examine the impact of the catalytic activities of HDAC1 and HDAC2, we generated knock-in mice expressing catalytically inactive isoforms, which are still incorporated into the HDAC1/HDAC2 corepressor complexes. Surprisingly, heterozygous mice expressing catalytically inactive HDAC2 die within a few hours after birth, while heterozygous HDAC1 mutant mice are indistinguishable from wild-type littermates. Heterozygous HDAC2 mutant mice show an unaltered composition but reduced associated deacetylase activity of corepressor complexes and exhibit a more severe phenotype than HDAC2-null mice. They display changes in brain architecture accompanied by premature expression of the key regulator protein kinase C delta. Our study reveals a dominant negative effect of catalytically inactive HDAC2 on specific corepressor complexes resulting in histone hyperacetylation, transcriptional derepression, and, ultimately, perinatal lethality., (Copyright © 2016 Hagelkruys et al.)
- Published
- 2015
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38. A novel Cd8-cis-regulatory element preferentially directs expression in CD44hiCD62L+ CD8+ T cells and in CD8αα+ dendritic cells.
- Author
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Sakaguchi S, Hombauer M, Hassan H, Tanaka H, Yasmin N, Naoe Y, Bilic I, Moser MA, Hainberger D, Mayer H, Seiser C, Bergthaler A, Taniuchi I, and Ellmeier W
- Subjects
- Animals, Base Sequence, CD8 Antigens biosynthesis, Chromosome Mapping, Core Binding Factor Alpha 3 Subunit metabolism, Dogs, Enhancer Elements, Genetic, Genes, Reporter, Humans, Hyaluronan Receptors analysis, Immunologic Memory, L-Selectin analysis, Mice, Mice, Transgenic, Molecular Sequence Data, Protein Interaction Mapping, Rats, Repressor Proteins metabolism, Sequence Alignment, Sequence Homology, Nucleic Acid, Species Specificity, T-Lymphocyte Subsets metabolism, Tumor Suppressor Proteins metabolism, CD8 Antigens genetics, CD8-Positive T-Lymphocytes metabolism, Conserved Sequence, Dendritic Cells metabolism, Gene Expression Regulation, Regulatory Sequences, Nucleic Acid genetics
- Abstract
CD8 coreceptor expression is dynamically regulated during thymocyte development and is tightly controlled by the activity of at least 5 different cis-regulatory elements. Despite the detailed characterization of the Cd8 loci, the regulation of the complex expression pattern of CD8 cannot be fully explained by the activity of the known Cd8 enhancers. In this study, we revisited the Cd8ab gene complex with bioinformatics and transgenic reporter gene expression approaches to search for additional Cd8 cis-regulatory elements. This led to the identification of an ECR (ECR-4), which in transgenic reporter gene expression assays, directed expression preferentially in CD44(hi)CD62L(+) CD8(+) T cells, including innate-like CD8(+) T cells. ECR-4, designated as Cd8 enhancer E8VI, was bound by Runx/CBFβ complexes and Bcl11b, indicating that E8VI is part of the cis-regulatory network that recruits transcription factors to the Cd8ab gene complex in CD8(+) T cells. Transgenic reporter expression was maintained in LCMV-specific CD8(+) T cells upon infection, although short-term, in vitro activation led to a down-regulation of E8VI activity. Finally, E8VI directed transgene expression also in CD8αα(+) DCs but not in CD8αα-expressing IELs. Taken together, we have identified a novel Cd8 enhancer that directs expression in CD44(hi)CD62L(+) CD8(+) T cells, including innate-like and antigen-specific effector/memory CD8(+) T cells and in CD8αα(+) DCs, and thus, our data provide further insight into the cis-regulatory networks that control CD8 expression., (© Society for Leukocyte Biology.)
- Published
- 2015
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39. H3S28 phosphorylation is a hallmark of the transcriptional response to cellular stress.
- Author
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Sawicka A, Hartl D, Goiser M, Pusch O, Stocsits RR, Tamir IM, Mechtler K, and Seiser C
- Subjects
- 3T3 Cells, Acetylation, Animals, Chromatin Immunoprecipitation, Fibroblasts cytology, Fibroblasts metabolism, Gene Expression Profiling, Gene Ontology, Genome-Wide Association Study, HeLa Cells, High-Throughput Nucleotide Sequencing, Histone Deacetylases genetics, Histone Deacetylases metabolism, Humans, MAP Kinase Signaling System genetics, Mice, Oligonucleotide Array Sequence Analysis, Phosphorylation, Promoter Regions, Genetic genetics, Ribosomal Protein S6 Kinases, 90-kDa genetics, Ribosomal Protein S6 Kinases, 90-kDa metabolism, Histones metabolism, Serine metabolism, Stress, Physiological genetics, Transcriptional Activation
- Abstract
The selectivity of transcriptional responses to extracellular cues is reflected by the deposition of stimulus-specific chromatin marks. Although histone H3 phosphorylation is a target of numerous signaling pathways, its role in transcriptional regulation remains poorly understood. Here, for the first time, we report a genome-wide analysis of H3S28 phosphorylation in a mammalian system in the context of stress signaling. We found that this mark targets as many as 50% of all stress-induced genes, underlining its importance in signal-induced transcription. By combining ChIP-seq, RNA-seq, and mass spectrometry we identified the factors involved in the biological interpretation of this histone modification. We found that MSK1/2-mediated phosphorylation of H3S28 at stress-responsive promoters contributes to the dissociation of HDAC corepressor complexes and thereby to enhanced local histone acetylation and subsequent transcriptional activation of stress-induced genes. Our data reveal a novel function of the H3S28ph mark in the activation of mammalian genes in response to MAP kinase pathway activation., (© 2014 Sawicka et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2014
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40. HDAC1 controls CD8+ T cell homeostasis and antiviral response.
- Author
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Tschismarov R, Firner S, Gil-Cruz C, Göschl L, Boucheron N, Steiner G, Matthias P, Seiser C, Ludewig B, and Ellmeier W
- Subjects
- Animals, Antiviral Agents therapeutic use, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Cell Proliferation, Hyaluronan Receptors metabolism, Interferon-gamma metabolism, Interleukin-2 metabolism, Ionomycin pharmacology, Lymphocytic Choriomeningitis drug therapy, Lymphocytic Choriomeningitis immunology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Tumor Necrosis Factor-alpha metabolism, Antiviral Agents pharmacology, CD8-Positive T-Lymphocytes drug effects, Histone Deacetylase 1 metabolism
- Abstract
Reversible lysine acetylation plays an important role in the regulation of T cell responses. HDAC1 has been shown to control peripheral T helper cells, however the role of HDAC1 in CD8+ T cell function remains elusive. By using conditional gene targeting approaches, we show that LckCre-mediated deletion of HDAC1 led to reduced numbers of thymocytes as well as peripheral T cells, and to an increased fraction of CD8+CD4- cells within the CD3/TCRβlo population, indicating that HDAC1 is essential for the efficient progression of immature CD8+CD4- cells to the DP stage. Moreover, CD44hi effector CD8+ T cells were enhanced in mice with a T cell-specific deletion of HDAC1 under homeostatic conditions and HDAC1-deficient CD44hi CD8+ T cells produced more IFNγ upon ex vivo PMA/ionomycin stimulation in comparison to wild-type cells. Naïve (CD44l°CD62L+) HDAC1-null CD8+ T cells displayed a normal proliferative response, produced similar amounts of IL-2 and TNFα, slightly enhanced amounts of IFNγ, and their in vivo cytotoxicity was normal in the absence of HDAC1. However, T cell-specific loss of HDAC1 led to a reduced anti-viral CD8+ T cell response upon LCMV infection and impaired expansion of virus-specific CD8+ T cells. Taken together, our data indicate that HDAC1 is required for the efficient generation of thymocytes and peripheral T cells, for proper CD8+ T cell homeostasis and for an efficient in vivo expansion and activation of CD8+ T cells in response to LCMV infection.
- Published
- 2014
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41. Sensing core histone phosphorylation - a matter of perfect timing.
- Author
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Sawicka A and Seiser C
- Subjects
- 14-3-3 Proteins genetics, Acetylation, Chromatin genetics, Chromatin metabolism, DNA Damage, Eukaryotic Cells cytology, Eukaryotic Cells metabolism, Histones genetics, Humans, Methylation, Mitosis, Phosphorylation, Protein Binding, Protein Interaction Domains and Motifs, Signal Transduction, Transcription, Genetic, 14-3-3 Proteins metabolism, Chromatin chemistry, Epigenesis, Genetic, Histones metabolism, Protein Processing, Post-Translational
- Abstract
Systematic analysis of histone modifications has revealed a plethora of posttranslational modifications that mediate changes in chromatin structure and gene expression. Histone phosphorylation is a transient histone modification that becomes induced by extracellular signals, DNA damage or entry into mitosis. Importantly, phosphorylation of histone proteins does lead not only to the binding of specific reader proteins but also to changes in the affinity for readers or writers of other histone modifications. This induces a cross-talk between different chromatin modifications that allows the spatio-temporal control of chromatin-associated events. In this review we will summarize the progress in our current knowledge of factors sensing reversible histone phosphorylation in different biological scenarios. This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
42. CD4(+) T cell lineage integrity is controlled by the histone deacetylases HDAC1 and HDAC2.
- Author
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Boucheron N, Tschismarov R, Goeschl L, Moser MA, Lagger S, Sakaguchi S, Winter M, Lenz F, Vitko D, Breitwieser FP, Müller L, Hassan H, Bennett KL, Colinge J, Schreiner W, Egawa T, Taniuchi I, Matthias P, Seiser C, and Ellmeier W
- Subjects
- Animals, Cell Differentiation genetics, Cell Lineage genetics, Cells, Cultured, Core Binding Factor alpha Subunits metabolism, Core Binding Factor beta Subunit metabolism, Cytokines metabolism, Cytotoxicity, Immunologic genetics, Histocompatibility Antigens Class II genetics, Histocompatibility Antigens Class II metabolism, Histone Deacetylase 1 genetics, Histone Deacetylase 2 genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Protein Binding, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Histone Deacetylase 1 metabolism, Histone Deacetylase 2 metabolism, Th1 Cells immunology
- Abstract
Molecular mechanisms that maintain lineage integrity of helper T cells are largely unknown. Here we show histone deacetylases 1 and 2 (HDAC1 and HDAC2) as crucial regulators of this process. Loss of HDAC1 and HDAC2 during late T cell development led to the appearance of major histocompatibility complex (MHC) class II-selected CD4(+) helper T cells that expressed CD8-lineage genes such as Cd8a and Cd8b1. HDAC1 and HDAC2-deficient T helper type 0 (TH0) and TH1 cells further upregulated CD8-lineage genes and acquired a CD8(+) effector T cell program in a manner dependent on Runx-CBFβ complexes, whereas TH2 cells repressed features of the CD8(+) lineage independently of HDAC1 and HDAC2. These results demonstrate that HDAC1 and HDAC2 maintain integrity of the CD4 lineage by repressing Runx-CBFβ complexes that otherwise induce a CD8(+) effector T cell-like program in CD4(+) T cells.
- Published
- 2014
- Full Text
- View/download PDF
43. Transcription and beyond: the role of mammalian class I lysine deacetylases.
- Author
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Moser MA, Hagelkruys A, and Seiser C
- Subjects
- Animals, Histone Deacetylases chemistry, Histones metabolism, Humans, Substrate Specificity, Histone Deacetylases metabolism, Lysine metabolism, Mammals metabolism, Transcription, Genetic
- Abstract
The Rpd3-like members of the class I lysine deacetylase family are important regulators of chromatin structure and gene expression and have pivotal functions in the control of proliferation, differentiation and development. The highly related class I deacetylases HDAC1 and HDAC2 have partially overlapping but also isoform-specific roles in diverse biological processes, whereas HDAC3 and HDAC8 have unique functions. This review describes the role of class I KDACs in the regulation of transcription as well as their non-transcriptional functions, in particular their contributions to splicing, mitosis/meiosis, replication and DNA repair. During the past years, a number of mouse loss-of-function studies provided new insights into the individual roles of class I deacetylases in cell cycle control, differentiation and tumorigenesis. Simultaneous ablation of HDAC1 and HDAC2 or single deletion of Hdac3 severely impairs cell cycle progression in all proliferating cell types indicating that these class I deacetylases are promising targets for small molecule inhibitors as anti-tumor drugs.
- Published
- 2014
- Full Text
- View/download PDF
44. A single allele of Hdac2 but not Hdac1 is sufficient for normal mouse brain development in the absence of its paralog.
- Author
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Hagelkruys A, Lagger S, Krahmer J, Leopoldi A, Artaker M, Pusch O, Zezula J, Weissmann S, Xie Y, Schöfer C, Schlederer M, Brosch G, Matthias P, Selfridge J, Lassmann H, Knoblich JA, and Seiser C
- Subjects
- Acetophenones pharmacology, Animals, Animals, Newborn, Apoptosis drug effects, Apoptosis genetics, Benzopyrans pharmacology, Brain metabolism, Brain pathology, Co-Repressor Proteins metabolism, DNA Damage genetics, Embryo Loss enzymology, Embryo Loss pathology, Gene Deletion, Gene Expression Regulation, Developmental drug effects, Gene Expression Regulation, Enzymologic drug effects, Histone Deacetylase 1 genetics, Histone Deacetylase 2 metabolism, Mice, Mice, Inbred C57BL, Phenotype, Protein Kinase C-delta antagonists & inhibitors, Protein Kinase C-delta genetics, Protein Kinase C-delta metabolism, Up-Regulation drug effects, Up-Regulation genetics, Alleles, Brain embryology, Brain enzymology, Histone Deacetylase 1 metabolism, Histone Deacetylase 2 genetics, Sequence Homology, Amino Acid
- Abstract
The histone deacetylases HDAC1 and HDAC2 are crucial regulators of chromatin structure and gene expression, thereby controlling important developmental processes. In the mouse brain, HDAC1 and HDAC2 exhibit different developmental stage- and lineage-specific expression patterns. To examine the individual contribution of these deacetylases during brain development, we deleted different combinations of Hdac1 and Hdac2 alleles in neural cells. Ablation of Hdac1 or Hdac2 by Nestin-Cre had no obvious consequences on brain development and architecture owing to compensation by the paralog. By contrast, combined deletion of Hdac1 and Hdac2 resulted in impaired chromatin structure, DNA damage, apoptosis and embryonic lethality. To dissect the individual roles of HDAC1 and HDAC2, we expressed single alleles of either Hdac1 or Hdac2 in the absence of the respective paralog in neural cells. The DNA-damage phenotype observed in double knockout brains was prevented by expression of a single allele of either Hdac1 or Hdac2. Strikingly, Hdac1(-/-)Hdac2(+/-) brains showed normal development and no obvious phenotype, whereas Hdac1(+/-)Hdac2(-/-) mice displayed impaired brain development and perinatal lethality. Hdac1(+/-)Hdac2(-/-) neural precursor cells showed reduced proliferation and premature differentiation mediated by overexpression of protein kinase C, delta, which is a direct target of HDAC2. Importantly, chemical inhibition or knockdown of protein kinase C delta was sufficient to rescue the phenotype of neural progenitor cells in vitro. Our data indicate that HDAC1 and HDAC2 have a common function in maintaining proper chromatin structures and show that HDAC2 has a unique role by controlling the fate of neural progenitors during normal brain development.
- Published
- 2014
- Full Text
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45. Divergent roles of HDAC1 and HDAC2 in the regulation of epidermal development and tumorigenesis.
- Author
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Winter M, Moser MA, Meunier D, Fischer C, Machat G, Mattes K, Lichtenberger BM, Brunmeir R, Weissmann S, Murko C, Humer C, Meischel T, Brosch G, Matthias P, Sibilia M, and Seiser C
- Subjects
- Alopecia genetics, Animals, Apoptosis genetics, Cell Lineage, Co-Repressor Proteins, Disease Models, Animal, Epidermis enzymology, Epidermis pathology, Gene Expression Regulation, Genes, Tumor Suppressor, Genes, p53, Hair Follicle pathology, Histone Deacetylase 1 genetics, Histone Deacetylase 2 genetics, Keratosis genetics, Keratosis pathology, Mice, Mice, Knockout, Mice, Transgenic, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism, Skin Neoplasms pathology, Epidermis growth & development, Histone Deacetylase 1 metabolism, Histone Deacetylase 2 metabolism, Skin Neoplasms genetics
- Abstract
The histone deacetylases HDAC1 and HDAC2 remove acetyl moieties from lysine residues of histones and other proteins and are important regulators of gene expression. By deleting different combinations of Hdac1 and Hdac2 alleles in the epidermis, we reveal a dosage-dependent effect of HDAC1/HDAC2 activity on epidermal proliferation and differentiation. Conditional ablation of either HDAC1 or HDAC2 in the epidermis leads to no obvious phenotype due to compensation by the upregulated paralogue. Strikingly, deletion of a single Hdac2 allele in HDAC1 knockout mice results in severe epidermal defects, including alopecia, hyperkeratosis, hyperproliferation and spontaneous tumour formation. These mice display impaired Sin3A co-repressor complex function, increased levels of c-Myc protein, p53 expression and apoptosis in hair follicles (HFs) and misregulation of HF bulge stem cells. Surprisingly, ablation of HDAC1 but not HDAC2 in a skin tumour model leads to accelerated tumour development. Our data reveal a crucial function of HDAC1/HDAC2 in the control of lineage specificity and a novel role of HDAC1 as a tumour suppressor in the epidermis.
- Published
- 2013
- Full Text
- View/download PDF
46. A role for paralog-specific sumoylation in histone deacetylase 1 stability.
- Author
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Citro S, Jaffray E, Hay RT, Seiser C, and Chiocca S
- Subjects
- Blotting, Western, Cell Line, Tumor, HeLa Cells, Humans, Immunoprecipitation, Protein Binding, Protein Stability, SUMO-1 Protein metabolism, Small Ubiquitin-Related Modifier Proteins metabolism, Sumoylation genetics, Sumoylation physiology, Ubiquitination, Histone Deacetylase 1 metabolism
- Abstract
Histone deacetylase 1 (HDAC1) is an essential epigenetic regulator belonging to a highly conserved family of deacetylases. Increased HDAC1 activity and expression often correlates with neoplastic transformation. Here we show how specific modification of HDAC1 by SUMO1, but not by SUMO2, facilitates HDAC1 degradation. Our findings reveal that SUMO1, but not SUMO2, conjugation to HDAC1 promotes HDAC1 ubiquitination and degradation. This is suggested by the observation that in non-tumorigenic mammary epithelial cells HDAC1 is preferentially conjugated to SUMO1 leading to HDAC1 proteolysis, whereas in breast cancer cells HDAC1 is more conjugated to SUMO2, promoting HDAC1 protein stability. SUMO E3 ligases play an important role in paralog-specific conjugation; in particular, the SUMO E3 ligase PIASy, which is overexpressed in breast cancer cells, selectively promotes the conjugation of HDAC1 to SUMO2. Therefore, cell environment affects paralog-specific sumoylation of HDAC1, whose conjugation to SUMO1 but not to SUMO2 facilitates its protein turnover. Our findings uncover a role for paralog-specific sumoylation of HDAC1 whose significance is emphasized by the use of HDAC inhibitors as anticancer drugs.
- Published
- 2013
- Full Text
- View/download PDF
47. Dynamic distribution of HDAC1 and HDAC2 during mitosis: association with F-actin.
- Author
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He S, Khan DH, Winter S, Seiser C, and Davie JR
- Subjects
- Aurora Kinase B, Aurora Kinases, Chromosomes, Human metabolism, Epigenesis, Genetic, HeLa Cells, Histones metabolism, Humans, Immunohistochemistry, MCF-7 Cells, Mitosis genetics, Phosphorylation, Protein Serine-Threonine Kinases metabolism, Actins metabolism, Histone Deacetylase 1 metabolism, Histone Deacetylase 2 metabolism, Mitosis physiology
- Abstract
During mitosis, histone deacetylase 2 (HDAC2) becomes highly phosphorylated through the action of CK2, and HDAC1 and 2 are displaced from mitotic chromosomes. HDAC1 and 2 are components of corepressor complexes, which function with lysine acetyltransferases to catalyze dynamic protein acetylation and regulate gene expression. In this study, we show that HDAC1 and 2 associate with F-actin in mitotic cells. Inhibition of Aurora B or protein kinase CK2 did not prevent the displacement of HDAC1 and 2 from mitotic chromosomes in HeLa cells. Further, proteins of the HDAC1 and 2 corepressor complexes and transcription factors recruiting these corepressors to chromatin were dissociated from mitotic chromosomes independent of Aurora B activity. HDAC1 and 2 returned to the nuclei of daughter cells during lamin A/C reassembly and before Sp1, Sp3, and RNA polymerase II. Our results show that HDAC1 and 2 corepressor complexes are removed from the mitotic chromosomes and are available early in the events leading to the re-establishment of the gene expression program in daughter cells., (Copyright © 2012 Wiley Periodicals, Inc.)
- Published
- 2013
- Full Text
- View/download PDF
48. Protein kinase CK2 regulates the dimerization of histone deacetylase 1 (HDAC1) and HDAC2 during mitosis.
- Author
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Khan DH, He S, Yu J, Winter S, Cao W, Seiser C, and Davie JR
- Subjects
- Casein Kinase I antagonists & inhibitors, Casein Kinase I genetics, Chromosomes, Human genetics, Co-Repressor Proteins, HEK293 Cells, HeLa Cells, Histone Deacetylase 1 genetics, Histone Deacetylase 2 genetics, Humans, Mi-2 Nucleosome Remodeling and Deacetylase Complex genetics, Mi-2 Nucleosome Remodeling and Deacetylase Complex metabolism, Mutation, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Phosphorylation physiology, Repressor Proteins genetics, Repressor Proteins metabolism, Sin3 Histone Deacetylase and Corepressor Complex genetics, Sin3 Histone Deacetylase and Corepressor Complex metabolism, Casein Kinase I metabolism, Chromosomes, Human enzymology, Histone Deacetylase 1 metabolism, Histone Deacetylase 2 metabolism, Mitosis physiology, Protein Multimerization physiology
- Abstract
Histone deacetylase 1 (HDAC1) and HDAC2 are components of corepressor complexes that are involved in chromatin remodeling and regulation of gene expression by regulating dynamic protein acetylation. HDAC1 and -2 form homo- and heterodimers, and their activity is dependent upon dimer formation. Phosphorylation of HDAC1 and/or HDAC2 in interphase cells is required for the formation of HDAC corepressor complexes. In this study, we show that during mitosis, HDAC2 and, to a lesser extent, HDAC1 phosphorylation levels dramatically increase. When HDAC1 and -2 are displaced from the chromosome during metaphase, they dissociate from each other, but each enzyme remains in association with components of the HDAC corepressor complexes Sin3, NuRD, and CoREST as homodimers. Enzyme inhibition studies and mutational analyses demonstrated that protein kinase CK2-catalyzed phosphorylation of HDAC1 and -2 is crucial for the dissociation of these two enzymes. These results suggest that corepressor complexes, including HDAC1 or HDAC2 homodimers, might target different cellular proteins during mitosis.
- Published
- 2013
- Full Text
- View/download PDF
49. Embryonic stem cells facilitate the isolation of persistent clonal cardiovascular progenitor cell lines and leukemia inhibitor factor maintains their self-renewal and myocardial differentiation potential in vitro.
- Author
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Hoebaus J, Heher P, Gottschamel T, Scheinast M, Auner H, Walder D, Wiedner M, Taubenschmid J, Miksch M, Sauer T, Schultheis M, Kuzmenkin A, Seiser C, Hescheler J, and Weitzer G
- Subjects
- Animals, Cell Differentiation physiology, Cell Line, Cytological Techniques methods, Embryo, Mammalian, Embryonic Stem Cells metabolism, Endothelial Cells cytology, Endothelial Cells metabolism, Female, Fibroblasts cytology, Fibroblasts metabolism, Humans, Male, Mice, Mice, Inbred C57BL, Microscopy, Confocal methods, Myocytes, Cardiac metabolism, Embryonic Stem Cells cytology, Leukemia Inhibitory Factor metabolism, Myocytes, Cardiac cytology
- Abstract
Compelling evidence for the existence of somatic stem cells in the heart of different mammalian species has been provided by numerous groups; however, so far it has not been possible to maintain these cells as self-renewing and phenotypically stable clonal cell lines in vitro. Thus, we sought to identify a surrogate stem cell niche for the isolation and persistent maintenance of stable clonal cardiovascular progenitor cell lines, enabling us to study the mechanism of self-renewal and differentiation in these cells. Using postnatal murine hearts with a selectable marker as the stem cell source and embryonic stem cells and leukemia inhibitory factor (LIF)-secreting fibroblasts as a surrogate niche, we succeeded in the isolation of stable clonal cardiovascular progenitor cell lines. These cell lines self-renew in an LIF-dependent manner. They express both stemness transcription factors Oct4, Sox2, and Nanog and early myocardial transcription factors Nkx2.5, GATA4, and Isl-1 at the same time. Upon LIF deprivation, they exclusively differentiate to functional cardiomyocytes and endothelial and smooth muscle cells, suggesting that these cells are mesodermal intermediates already committed to the cardiogenic lineage. Cardiovascular progenitor cell lines can be maintained for at least 149 passages over 7 years without phenotypic changes, in the presence of LIF-secreting fibroblasts. Isolation of wild-type cardiovascular progenitor cell lines from adolescent and old mice has finally demonstrated the general feasibility of this strategy for the isolation of phenotypically stable somatic stem cell lines., (Copyright © 2013 S. Karger AG, Basel.)
- Published
- 2013
- Full Text
- View/download PDF
50. Histone deacetylase inhibitor Trichostatin A induces neural tube defects and promotes neural crest specification in the chicken neural tube.
- Author
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Murko C, Lagger S, Steiner M, Seiser C, Schoefer C, and Pusch O
- Subjects
- Animals, Apoptosis drug effects, Bone Morphogenetic Protein 4 genetics, Bone Morphogenetic Protein 4 metabolism, Cadherins genetics, Cadherins metabolism, Chick Embryo, Neural Crest embryology, Neural Tube drug effects, Neural Tube embryology, Neuroepithelial Cells drug effects, Neuroepithelial Cells metabolism, Transcription Factors genetics, Transcription Factors metabolism, Histone Deacetylase Inhibitors toxicity, Hydroxamic Acids toxicity, Neural Crest drug effects, Neural Tube Defects chemically induced
- Abstract
Epigenetic mechanisms serve as key regulatory elements during vertebrate embryogenesis. Histone acetylation levels, controlled by the opposing action of histone acetyl transferases (HATs) and histone deacetylases (HDACs), influence the accessibility of DNA to transcription factors and thereby dynamically regulate transcriptional programs. HDACs execute important functions in the control of proliferation, differentiation, and the establishment of cell identities during embryonic development. To investigate the global role of the HDAC family during neural tube development, we employed Trichostatin A (TSA) to locally block enzymatic HDAC activity in chick embryos in ovo. We found that TSA treatment induces neural tube defects at the level of the posterior neuropore, ranging from slight undulations to a complete failure of neural tube closure. This phenotype is accompanied by morphological changes in neuroepithelial cells and induction of apoptosis. As a molecular consequence of HDAC inhibition, we observed a timely deregulated cadherin switching in the dorsal neural tube, illustrated by induction of Cadherin 6B as well as reciprocal downregulation of N-Cadherin expression. Concomitantly, several neural crest specific markers, including Bmp4, Pax3, Sox9 and Sox10 are induced, causing a premature loss of epithelial characteristics. Our findings provide evidence that HDAC function is crucial to control the regulatory circuits operating during trunk neural crest development and neural tube closure., (Copyright © 2012 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
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