scholarly journals Isolation of a novel histone deacetylase reveals that class I and class II deacetylases promote SMRT-mediated repression

2000 ◽  
Vol 14 (1) ◽  
pp. 55-66 ◽  
Author(s):  
Hung-Ying Kao ◽  
Michael Downes ◽  
Peter Ordentlich ◽  
Ronald M. Evans
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Mammalian Cells ◽  
Class Ii ◽  
Class I ◽  
Nuclear Compartment ◽  
New Family ◽  
Repressive Effect ◽  
Two Hybrid

The transcriptional corepressor SMRT functions by mediating the repressive effect of transcription factors involved in diverse signaling pathways. The mechanism by which SMRT represses basal transcription has been proposed to involve the indirect recruitment of histone deacetylase HDAC1 via the adaptor mSin3A. In contrast to this model, a two-hybrid screen on SMRT-interacting proteins resulted in the isolation of the recently described HDAC5 and a new family member termed HDAC7. Molecular and biochemical results indicate that this interaction is direct and in vivo evidence colocalizes SMRT, mHDAC5, and mHDAC7 to a distinct nuclear compartment. Surprisingly, HDAC7 can interact with mSin3A in yeast and in mammalian cells, suggesting association of multiple repression complexes. Taken together, our results provide the first evidence that SMRT-mediated repression is promoted by class I and class II histone deacetylases and that SMRT can recruit class II histone deacetylases in a mSin3A-independent fashion.

scholarly journals Inhibition of Polyomavirus ori-Dependent DNA Replication by mSin3B

2002 ◽  
Vol 76 (23) ◽  
pp. 11809-11818 ◽  
Author(s):  
An-Yong Xie ◽  
William R. Folk
Keyword(s):  
Dna Replication ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Class Ii ◽  
T Antigen ◽  
Class I ◽  
Large T Antigen ◽  
Transcriptional Corepressor ◽  
Independent Mechanism

ABSTRACT When tethered in cis to DNA, the transcriptional corepressor mSin3B inhibits polyomavirus (Py) ori-dependent DNA replication in vivo. Histone deacetylases (HDACs) appear not to be involved, since tethering class I and class II HDACs in cis does not inhibit replication and treating the cells with trichostatin A does not specifically relieve inhibition by mSin3B. However, the mSin3B L59P mutation that impairs mSin3B interaction with N-CoR/SMRT abrogates inhibition of replication, suggesting the involvement of N-CoR/SMRT. Py large T antigen interacts with mSin3B, suggesting an HDAC-independent mechanism by which mSin3B inhibits DNA replication.

scholarly journals HDACs class II-selective inhibition alters nuclear receptor-dependent differentiation

2010 ◽  
Vol 45 (4) ◽  
pp. 219-228 ◽  
Author(s):  
Angela Nebbioso ◽  
Carmela Dell'Aversana ◽  
Anne Bugge ◽  
Roberta Sarno ◽  
Sergio Valente ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Selective Inhibition ◽  
Class Ii ◽  
Class I ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
F9 Cells ◽  
Anti Cancer ◽  
Cardiovascular Defects

Epigenetic deregulation contributes to diseases including cancer, neurodegeneration, osteodystrophy, cardiovascular defects, and obesity. For this reason, several inhibitors for histone deacetylases (HDACs) are being validated as novel anti-cancer drugs in clinical studies and display important anti-proliferative activities. While most inhibitors act on both class I, II, and IV HDACs, evidence is accumulating that class I is directly involved in regulation of cell growth and death, whereas class II members regulate differentiation processes, such as muscle and neuronal differentiation. Here, we show that the novel class II-selective inhibitor MC1568 interferes with the RAR- and peroxisome proliferator-activated receptor γ (PPARγ)-mediated differentiation-inducing signaling pathways. In F9 cells, this inhibitor specifically blocks endodermal differentiation despite not affecting retinoic acid-induced maturation of promyelocytic NB4 cells. In 3T3-L1 cells, MC1568 attenuates PPARγ-induced adipogenesis, while the class I-selective MS275 blocked adipogenesis completely thus revealing a different mode of action and/or target profile of the two classes of HDACs. Using in vivo reporting PPRE-Luc mice, we find that MC1568 impairs PPARγ signaling mostly in the heart and adipose tissues. These results illustrate how HDAC functions can be dissected by selective inhibitors.

Class II histone deacetylases: Structure, function, and regulation

2001 ◽  
Vol 79 (3) ◽  
pp. 243-252 ◽  
Author(s):  
Nicholas R Bertos ◽  
Audrey H Wang ◽  
Xiang-Jiao Yang
Keyword(s):  
Structure Function ◽  
Histone Deacetylases ◽  
Mammalian Cells ◽  
Dynamic Control ◽  
Class Ii ◽  
Protein Acetylation ◽  
Cellular Processes ◽  
Subcellular Compartmentalization ◽  
Transcriptional Corepressors

Acetylation of histones, as well as non-histone proteins, plays important roles in regulating various cellular processes. Dynamic control of protein acetylation levels in vivo occurs through the opposing actions of histone acetyltransferases and histone deacetylases (HDACs). In the past few years, distinct classes of HDACs have been identified in mammalian cells. Class I members, such as HDAC1, HDAC2, HDAC3, and HDAC8, are well-known enzymatic transcriptional corepressors homologous to yeast Rpd3. Class II members, including HDAC4, HDAC5, HDAC6, HDAC7, and HDAC9, possess domains similar to the deacetylase domain of yeast Hda1. HDAC4, HDAC5, and HDAC7 function as transcriptional corepressors that interact with the MEF2 transcription factors and the N-CoR, BCoR, and CtBP corepressors. Intriguingly, HDAC4, HDAC5, and probably HDAC7 are regulated through subcellular compartmentalization controlled by site-specific phosphorylation and binding of 14-3-3 proteins; the regulation of these HDACs is thus directly linked to cellular signaling networks. Both HDAC6 and HDAC9 possess unique structural modules, so they may have special biological functions. Comprehension of the structure, function, and regulation of class II deacetylases is important for elucidating how acetylation regulates functions of histones and other proteins in vivo.Key words: histone acetylation, protein acetylation, histone deacetylase, 14-3-3 proteins.

scholarly journals Functional Divergence between Histone Deacetylases in Fission Yeast by Distinct Cellular Localization and In Vivo Specificity

2002 ◽  
Vol 22 (7) ◽  
pp. 2170-2181 ◽  
Author(s):  
Pernilla Bjerling ◽  
Rebecca A. Silverstein ◽  
Geneviève Thon ◽  
Amy Caudy ◽  
Shiv Grewal ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Cellular Localization ◽  
Functional Divergence ◽  
Binding Pocket ◽  
Class Ii ◽  
Class I ◽  
Chromosome Loss ◽  
Level Of Activity ◽  
High Level

ABSTRACT Histone deacetylases (HDACs) are important for gene regulation and the maintenance of heterochromatin in eukaryotes. Schizosaccharomyces pombe was used as a model system to investigate the functional divergence within this conserved enzyme family. S. pombe has three HDACs encoded by the hda1+ , clr3+ , and clr6+ genes. Strains mutated in these genes have previously been shown to display strikingly different phenotypes when assayed for viability, chromosome loss, and silencing. Here, conserved differences in the substrate binding pocket identify Clr6 and Hda1 as class I HDACs, while Clr3 belongs in the class II family. Furthermore, these HDACs were shown to have strikingly different subcellular localization patterns. Hda1 was localized to the cytoplasm, while most of Clr3 resided throughout the nucleus. Finally, Clr6 was localized exclusively on the chromosomes in a spotted pattern. Interestingly, Clr3, the only HDAC present in the nucleolus, was required for ribosomal DNA (rDNA) silencing. Clr3 presumably acts directly on heterochromatin, since it colocalized with the centromere, mating-type region, and rDNA as visualized by in situ hybridization. In addition, Clr3 could be cross-linked to mat3 in chromatin immunoprecipitation experiments. Western analysis of bulk histone preparations indicated that Hda1 (class I) had a generally low level of activity in vivo and Clr6 (class I) had a high level of activity and broad in vivo substrate specificity, whereas Clr3 (class II) displayed its main activity on acetylated lysine 14 of histone H3. Thus, the distinct functions of the S. pombe HDACs are likely explained by their distinct cellular localization and their different in vivo specificities.

Inhibition of both class I and class II histone deacetylases is required to effectively inhibit osteoclast bone resorption in vivo and in vitro

Bone ◽  
2009 ◽  
Vol 44 ◽  
pp. S133-S134
Author(s):  
M.D. Cantley ◽  
D.P. Fairlie ◽  
M.P. Bartold ◽  
K.D. Rainsford ◽  
D.R. Haynes
Keyword(s):  
Bone Resorption ◽  
Histone Deacetylases ◽  
Class Ii ◽  
Class I

A rapid and reliable in vivo method for anti-GPLA (class I and class II antigens) antibody titration and GPLA typing

1983 ◽  
Vol 59 (2) ◽  
pp. 205-215 ◽  
Author(s):  
Thérèse Neveu ◽  
Michèle Lefroit-Joliy ◽  
Guy André Voisin
Keyword(s):  
Class Ii ◽  
Class I ◽  
Class Ii Antigens

scholarly journals Functional Interaction between Class II Histone Deacetylases and ICP0 of Herpes Simplex Virus Type 1

2004 ◽  
Vol 78 (13) ◽  
pp. 6744-6757 ◽  
Author(s):  
Patrick Lomonte ◽  
Joëlle Thomas ◽  
Pascale Texier ◽  
Cécile Caron ◽  
Saadi Khochbin ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Histone Deacetylases ◽  
Class Ii ◽  
Class I ◽  
Transfected Cells ◽  
Amino Terminal ◽  
Simplex Virus ◽  
Class I Hdacs

ABSTRACT This study describes the physical and functional interactions between ICP0 of herpes simplex virus type 1 and class II histone deacetylases (HDACs) 4, 5, and 7. Class II HDACs are mainly known for their participation in the control of cell differentiation through the regulation of the activity of the transcription factor MEF2 (myocyte enhancer factor 2), implicated in muscle development and neuronal survival. Immunofluorescence experiments performed on transfected cells showed that ICP0 colocalizes with and reorganizes the nuclear distribution of ectopically expressed class I and II HDACs. In addition, endogenous HDAC4 and at least one of its binding partners, the corepressor protein SMRT (for silencing mediator of retinoid and thyroid receptor), undergo changes in their nuclear distribution in ICP0-transfected cells. As a result, during infection endogenous HDAC4 colocalizes with ICP0. Coimmunoprecipitation and glutathione S-transferase pull-down assays confirmed that class II but not class I HDACs specifically interacted with ICP0 through their amino-terminal regions. This region, which is not conserved in class I HDACs but homologous to the MITR (MEF2-interacting transcription repressor) protein, is responsible for the repression, in a deacetylase-independent manner, of MEF2 by sequestering it under an inactive form in the nucleus. Consequently, we show that ICP0 is able to overcome the HDAC5 amino-terminal- and MITR-induced MEF2A repression in gene reporter assays. This is the first report of a viral protein interacting with and controlling the repressor activity of class II HDACs. We discuss the putative consequences of such an interaction for the biology of the virus both during lytic infection and reactivation from latency.

scholarly journals Epigenetic Metabolite Acetate Inhibits Class I/II Histone Deacetylases, Promotes Histone Acetylation, and Increases HIV-1 Integration in CD4+ T Cells

2017 ◽  
Vol 91 (16) ◽  
Author(s):  
Jean-François Bolduc ◽  
Laurent Hany ◽  
Corinne Barat ◽  
Michel Ouellet ◽  
Michel J. Tremblay
Keyword(s):  
T Cells ◽  
Histone Acetylation ◽  
Disease Progression ◽  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Class I ◽  
Hdac Activity ◽  
Hiv 1

ABSTRACT In this study, we investigated the effect of acetate, the most concentrated short-chain fatty acid (SCFA) in the gut and bloodstream, on the susceptibility of primary human CD4+ T cells to HIV-1 infection. We report that HIV-1 replication is increased in CD3/CD28-costimulated CD4+ T cells upon acetate treatment. This enhancing effect correlates with increased expression of the early activation marker CD69 and impaired class I/II histone deacetylase (HDAC) activity. In addition, acetate enhances acetylation of histones H3 and H4 and augments HIV-1 integration into the genome of CD4+ T cells. Thus, we propose that upon antigen presentation, acetate influences class I/II HDAC activity that transforms condensed chromatin into a more relaxed structure. This event leads to a higher level of viral integration and enhanced HIV-1 production. In line with previous studies showing reactivation of latent HIV-1 by SCFAs, we provide evidence that acetate can also increase the susceptibility of primary human CD4+ T cells to productive HIV-1 infection. IMPORTANCE Alterations in the fecal microbiota and intestinal epithelial damage involved in the gastrointestinal disorder associated with HIV-1 infection result in microbial translocation that leads to disease progression and virus-related comorbidities. Indeed, notably via production of short-chain fatty acids, bacteria migrating from the lumen to the intestinal mucosa could influence HIV-1 replication by epigenetic regulatory mechanisms, such as histone acetylation. We demonstrate that acetate enhances virus production in primary human CD4+ T cells. Moreover, we report that acetate impairs class I/II histone deacetylase activity and increases integration of HIV-1 DNA into the host genome. Therefore, it can be postulated that bacterial metabolites such as acetate modulate HIV-1-mediated disease progression.

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