scholarly journals Histone modifications affect timing of oligodendrocyte progenitor differentiation in the developing rat brain

2005 ◽  
Vol 169 (4) ◽  
pp. 577-589 ◽  
Author(s):  
Siming Shen ◽  
Jiadong Li ◽  
Patrizia Casaccia-Bonnefil
Keyword(s):  
Corpus Callosum ◽  
Histone Deacetylases ◽  
Recovery Period ◽  
Specific Inhibitor ◽  
Histone Deacetylation ◽  
Oligodendrocyte Differentiation ◽  
Differentiation Markers ◽  
Developing Rat ◽  
Myelin Gene

Timely differentiation of progenitor cells is critical for development. In this study we asked whether global epigenetic mechanisms regulate timing of progenitor cell differentiation into myelin-forming oligodendrocytes in vivo. Histone deacetylation was essential during a specific temporal window of development and was dependent on the enzymatic activity of histone deacetylases, whose expression was detected in the developing corpus callosum. During the first 10 postnatal days, administration of valproic acid (VPA), the specific inhibitor for histone deacetylase activity, resulted in significant hypomyelination with delayed expression of late differentiation markers and retained expression of progenitor markers. Differentiation resumed in VPA-injected rats if a recovery period was allowed. Administration of VPA after myelination onset had no effect on myelin gene expression and was consistent with changes of nucleosomal histones from reversible deacetylation to more stable methylation and chromatin compaction. Together, these data identify global modifications of nucleosomal histones critical for timing of oligodendrocyte differentiation and myelination in the developing corpus callosum.

scholarly journals The Growth Suppressor PML Represses Transcription by Functionally and Physically Interacting with Histone Deacetylases

2001 ◽  
Vol 21 (7) ◽  
pp. 2259-2268 ◽  
Author(s):  
Wen-Shu Wu ◽  
Sadeq Vallian ◽  
Edward Seto ◽  
Wen-Ming Yang ◽  
Diane Edmondson ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Cell Cycle Progression ◽  
Trichostatin A ◽  
Specific Inhibitor ◽  
Promyelocytic Leukemia ◽  
Histone Deacetylation ◽  
Growth Suppressor

ABSTRACT The growth suppressor promyelocytic leukemia protein (PML) is disrupted by the chromosomal translocation t(15;17) in acute promyelocytic leukemia (APL). PML plays a key role in multiple pathways of apoptosis and regulates cell cycle progression. The present study demonstrates that PML represses transcription by functionally and physically interacting with histone deacetylase (HDAC). Transcriptional repression mediated by PML can be inhibited by trichostatin A, a specific inhibitor of HDAC. PML coimmunoprecipitates a significant level of HDAC activity in several cell lines. PML is associated with HDAC in vivo and directly interacts with HDAC in vitro. The fusion protein PML-RARα encoded by the t(15;17) breakpoint interacts with HDAC poorly. PML interacts with all three isoforms of HDAC through specific domains, and its expression deacetylates histone H3 in vivo. Together, the results of our study show that PML modulates histone deacetylation and that loss of this function in APL alters chromatin remodeling and gene expression. This event may contribute to the development of leukemia.

scholarly journals Krüppel-like factor 4, Elk-1, and histone deacetylases cooperatively suppress smooth muscle cell differentiation markers in response to oxidized phospholipids

2008 ◽  
Vol 295 (5) ◽  
pp. C1175-C1182 ◽  
Author(s):  
Tadashi Yoshida ◽  
Qiong Gan ◽  
Gary K. Owens
Keyword(s):  
Smooth Muscle ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Phenotypic Switching ◽  
Marker Genes ◽  
Physical Interaction ◽  
Oxidized Phospholipids ◽  
Differentiation Markers ◽  
Differentiation Marker

Phenotypic switching of vascular smooth muscle cells (SMCs), such as increased proliferation, enhanced migration, and downregulation of SMC differentiation marker genes, is known to play a key role in the development of atherosclerosis. However, the factors and mechanisms controlling this process are not fully understood. We recently showed that oxidized phospholipids, including 1-palmitoyl-2-(5-oxovaleroyl)- sn-glycero-3-phosphocholine (POVPC), which accumulate in atherosclerotic lesions, are potent repressors of expression of SMC differentiation marker genes in cultured SMCs as well as in rat carotid arteries in vivo. Here, we examined the molecular mechanisms whereby POVPC induces suppression of SMC differentiation marker genes in cultured SMCs. Results showed that POVPC induced phosphorylation of ERK1/2 and Elk-1. The MEK inhibitors U-0126 and PD-98059 attenuated POVPC-induced suppression of smooth muscle ( SM) α-actin and SM-myosin heavy chain. POVPC also induced expression of Krüppel-like factor 4 (Klf4). Chromatin immunoprecipitation assays revealed that POVPC caused simultaneous binding of Elk-1 and Klf4 to the promoter region of the SM α-actin gene. Moreover, coimmunoprecipitation assays showed a physical interaction between Elk-1 and Klf4. Results in Klf4-null SMCs showed that blockade of both Klf4 induction and Elk-1 phosphorylation completely abolished POVPC-induced suppression of SMC differentiation marker genes. POVPC-induced suppression of SMC differentiation marker genes was also accompanied by hypoacetylation of histone H4 at the SM α-actin promoter, which was mediated by the recruitment of histone deacetylases (HDACs), HDAC2 and HDAC5. Coimmunoprecipitation assays showed that Klf4 interacted with HDAC5. Results provide evidence that Klf4, Elk-1, and HDACs coordinately mediate POVPC-induced suppression of SMC differentiation marker genes.

scholarly journals Multiple Histone Deacetylases and the CREB-binding Protein Regulate Pre-mRNA 3′-End Processing

2006 ◽  
Vol 282 (7) ◽  
pp. 4470-4478 ◽  
Author(s):  
Tadahiro Shimazu ◽  
Sueharu Horinouchi ◽  
Minoru Yoshida
Keyword(s):  
Mass Spectrometry ◽  
Complex Formation ◽  
Nuclear Localization ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Specific Inhibitor ◽  
Creb Binding Protein ◽  
Processing Machinery ◽  
Importin Α

Trichostatin A (TSA), a specific inhibitor of histone deacetylases (HDACs), induces acetylation of various non-histone proteins such as p53 and α-tubulin. We purified several acetylated proteins by the affinity to an anti-acetylated lysine (AcLys) antibody from cells treated with TSA and identified them by mass spectrometry. Here we report on acetylation of CFIm25, a component of mammalian cleavage factor Im (CF Im), and poly(A) polymerase (PAP), a polyadenylating enzyme for the pre-mRNA 3′-end. The residues acetylated in these proteins were mapped onto the regions required for interaction with each other. Whereas CBP acetylated these proteins, HDAC1, HDAC3, HDAC10, SIRT1, and SIRT2 were involved in in vivo deacetylation. Acetylation of the CFIm25 occurred depending on the cleavage factor complex formation. Importantly, the interaction between PAP and CF Im complex was decreased by acetylation. We also demonstrated that acetylation of PAP inhibited the nuclear localization of PAP by inhibiting the binding to the importin α/β complex. These results suggest that CBP and HDACs regulate the 3′-end processing machinery and modulate the localization of PAP through the acetylation and deacetylation cycle.

scholarly journals In Vivo 6-([18F]Fluoroacetamido)-1-hexanoicanilide PET Imaging of Altered Histone Deacetylase Activity in Chemotherapy-Induced Neurotoxicity

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Nobuyoshi Fukumitsu ◽  
Skye Hsin-Hsien Yeh ◽  
Leo Garcia Flores II ◽  
Uday Mukhopadhyay ◽  
Daniel Young ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Histone Deacetylases ◽  
Histone Deacetylation ◽  
Antitumor Effects ◽  
Neuroprotective Effects ◽  
Positron Emission ◽  
Group A ◽  
Expression Activity ◽  
Group B

Background. Histone deacetylases (HDACs) regulate gene expression by changing histone deacetylation status. Neurotoxicity is one of the major side effects of cisplatin, which reacts with deoxyribonucleic acid (DNA) and has excellent antitumor effects. Suberoylanilide hydroxamic acid (SAHA) is an HDAC inhibitor with neuroprotective effects against cisplatin-induced neurotoxicity. Purpose. We investigated how cisplatin with and without SAHA pretreatment affects HDAC expression/activity in the brain by using 6-([18F]fluoroacetamido)-1-hexanoicanilide ([18F]FAHA) as a positron emission tomography (PET) imaging agent for HDAC IIa. Materials and Methods. [18F]FAHA and [18F]fluoro-2-deoxy-2-D-glucose ([18F]FDG) PET studies were done in 24 mice on 2 consecutive days and again 1 week later. The mice were divided into three groups according to drug administration between the first and second imaging sessions (Group A: cisplatin 2 mg/kg, twice; Group B: cisplatin 4 mg/kg, twice; Group C: cisplatin 4 mg/kg, twice, and SAHA 300 mg/kg pretreatment, 4 times). Results. The Ki value of [18F]FAHA was increased and the percentage of injected dose/tissue g (% ID/g) of [18F]FDG was decreased in the brains of animals in Groups A and B. The Ki value of [18F]FAHA and % ID/g of [18F]FDG were not significantly different in Group C. Conclusions. [18F]FAHA PET clearly showed increased HDAC activity suggestive of cisplatin neurotoxicity in vivo, which was blocked by SAHA pretreatment.

scholarly journals p53-Dependent Transcriptional Repression of c-myc Is Required for G1 Cell Cycle Arrest

2005 ◽  
Vol 25 (17) ◽  
pp. 7423-7431 ◽  
Author(s):  
Jenny S. L. Ho ◽  
Weili Ma ◽  
Daniel Y. L. Mao ◽  
Samuel Benchimol
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Histone Deacetylation ◽  
Dependent Manner ◽  
Cycle Arrest ◽  
Mouse Tissues

ABSTRACT The ability of p53 to promote apoptosis and cell cycle arrest is believed to be important for its tumor suppression function. Besides activating the expression of cell cycle arrest and proapoptotic genes, p53 also represses a number of genes. Previous studies have shown an association between p53 activation and down-regulation of c-myc expression. However, the mechanism and physiological significance of p53-mediated c-myc repression remain unclear. Here, we show that c-myc is repressed in a p53-dependent manner in various mouse and human cell lines and mouse tissues. Furthermore, c-myc repression is not dependent on the expression of p21WAF1. Abrogating the repression of c-myc by ectopic c-myc expression interferes with the ability of p53 to induce G1 cell cycle arrest and differentiation but enhances the ability of p53 to promote apoptosis. We propose that p53-dependent cell cycle arrest is dependent not only on the transactivation of cell cycle arrest genes but also on the transrepression of c-myc. Chromatin immunoprecipitation assays indicate that p53 is bound to the c-myc promoter in vivo. We report that trichostatin A, an inhibitor of histone deacetylases, abrogates the ability of p53 to repress c-myc transcription. We also show that p53-mediated transcriptional repression of c-myc is accompanied by a decrease in the level of acetylated histone H4 at the c-myc promoter and by recruitment of the corepressor mSin3a. These data suggest that p53 represses c-myc transcription through a mechanism that involves histone deacetylation.

scholarly journals Mutations in Saccharomyces cerevisiae GeneSIR2 Can Have Differential Effects on In Vivo Silencing Phenotypes and In Vitro Histone Deacetylation Activity

2002 ◽  
Vol 13 (4) ◽  
pp. 1427-1438 ◽  
Author(s):  
Christopher M. Armstrong ◽  
Matt Kaeberlein ◽  
Shin Ichiro Imai ◽  
Leonard Guarente
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Histone Deacetylation ◽  
Conserved Residues ◽  
Core Domain ◽  
Sir Complex ◽  
In Vivo Effects ◽  
The Relationship

The yeast SIR2 gene and many of its homologs have been identified as NAD+-dependent histone deacetylases. To get a broader view of the relationship between the histone deacetylase activity of Sir2p and its in vivo functions we have mutated eight highly conserved residues in the core domain ofSIR2. These mutations have a range of effects on the ability of Sir2p to deacetylate histones in vitro and to silence genes at the telomeres and HM loci. Interestingly, there is not a direct correlation between the in vitro and in vivo effects in some of these mutations. We also show that the histone deacetylase activity of Sir2p is necessary for the proper localiztion of the SIR complex to the telomeres.

scholarly journals Recruitment of N-CoR/SMRT-TBLR1 Corepressor Complex by Unliganded Thyroid Hormone Receptor for Gene Repression during Frog Development

2004 ◽  
Vol 24 (8) ◽  
pp. 3337-3346 ◽  
Author(s):  
Akihiro Tomita ◽  
Daniel R. Buchholz ◽  
Yun-Bo Shi
Keyword(s):  
Thyroid Hormone ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Histone Deacetylation ◽  
Gene Repression ◽  
Vertebrate Development ◽  
Inducible Promoters

ABSTRACT The corepressors N-CoR (nuclear receptor corepressor) and SMRT (silencing mediator for retinoid and thyroid hormone receptors) interact with unliganded nuclear hormone receptors, including thyroid hormone (T3) receptor (TR). Several N-CoR/SMRT complexes containing histone deacetylases have been purified. The best studied among them are N-CoR/SMRT complexes containing TBL1 (transducin beta-like protein 1) or TBLR1 (TBL1-related protein). Despite extensive studies of these complexes, there has been no direct in vivo evidence for the interaction of TBL1 or TBLR1 with TR or the possible involvement of such complexes in gene repression by any nuclear receptors in any animals. Here, we used the frog oocyte system to demonstrate that unliganded TR interacts with TBLR1 and recruits TBLR1 to its chromatinized target promoter in vivo, accompanied by histone deacetylation and gene repression. We further provide evidence to show that the recruitment of TBLR1 or related proteins is important for repression by unliganded TR. To investigate the potential role for TBLR1 complexes during vertebrate development, we made use of T3-dependent amphibian metamorphosis as a model. We found that TBLR1, SMRT, and N-CoR are recruited to T3-inducible promoters in premetamorphic tadpoles and are released upon T3 treatment, which induces metamorphosis. More importantly, we demonstrate that the dissociation of N-CoR/SMRT-TBLR1 complexes from endogenous TR target promoters is correlated with the activation of these genes during spontaneous metamorphosis. Taken together, our studies provide in vivo evidence for targeted recruitment of N-CoR/SMRT-TBLR1 complexes by unliganded TR in transcriptional repression during vertebrate development.

scholarly journals The Capability of O-Acetyl-ADP-Ribose, an Epigenetic Metabolic Small Molecule, on Promoting the Further Spreading of Sir3 along the Telomeric Chromatin

Genes ◽  
2019 ◽  
Vol 10 (8) ◽  
pp. 577
Author(s):  
Tung ◽  
Wang ◽  
Lee ◽  
Tsai ◽  
Su ◽  
...  
Keyword(s):  
Small Molecule ◽  
Histone Deacetylases ◽  
Affinity Purification ◽  
Direct Interaction ◽  
Structural Rearrangement ◽  
Histone Deacetylation ◽  
Titration Calorimetry ◽  
On Chip

O-acetyl-ADP-ribose (AAR) is a metabolic small molecule relevant in epigenetics that is generated by NAD-dependent histone deacetylases, such as Sir2. The formation of silent heterochromatin in yeast requires histone deacetylation by Sir2, structural rearrangement of SIR complexes, spreading of SIR complexes along the chromatin, and additional maturation processing. AAR affects the interactions of the SIR-nucleosome in vitro and enhances the chromatin epigenetic silencing effect in vivo. In this study, using isothermal titration calorimetry (ITC) and dot blotting methods, we showed the direct interaction of AAR with Sir3. Furthermore, through chromatin immunoprecipitation (ChIP)-on-chip and chromatin affinity purification (ChAP)-on chip assays, we discovered that AAR is capable of increasing the extended spreading of Sir3 along telomeres, but not Sir2. In addition, the findings of a quantitative real-time polymerase chain reaction (qRT-PCR) and examinations of an in vitro assembly system of SIR-nucleosome heterochromatin filament were consistent with these results. This study provides evidence indicating another important effect of AAR in vivo. AAR may play a specific modulating role in the formation of silent SIR-nucleosome heterochromatin in yeast.

scholarly journals Inhibition of Histone Deacetylation Induces Constitutive Derepression of the Beta Interferon Promoter and Confers Antiviral Activity

2001 ◽  
Vol 75 (7) ◽  
pp. 3444-3452 ◽  
Author(s):  
Elena Shestakova ◽  
Marie-Thérèse Bandu ◽  
Janine Doly ◽  
Eliette Bonnefoy
Keyword(s):  
Virus Infection ◽  
De Novo ◽  
Trichostatin A ◽  
Specific Inhibitor ◽  
Histone Deacetylation ◽  
Histone H4 ◽  
Antiviral State ◽  
Beta Interferon ◽  
Silent State

ABSTRACT The induction of alpha/beta interferon (IFN-α/β) genes constitutes one of the first responses of the cell to virus infection. The IFN-β gene is constitutively repressed in uninfected cells and is transiently activated after virus infection. In this work we demonstrate that histone deacetylation regulates the silent state of the murine IFN-β gene. Using chromatin immunoprecipitation (ChIP) assays, we show a direct in vivo correlation between the transcriptionally silent state and a state of hypoacetylation of histone H4 on the IFN-β promoter region. Trichostatin A (TSA), a specific inhibitor of histone deacetylases, induced strong, constitutive derepression of the murine IFN-β promoter stably integrated into a chromatin context, as well as the hyperacetylation of histone H4, without requiring de novo protein synthesis. We also show in this work that TSA treatment strongly enhances the endogenous IFN level and confers an antiviral state to murine fibroblastic L929 cells. Inhibition of histone deacetylation with TSA protected the cells against the lost of viability induced by vesicular stomatitis virus (VSV) and inhibited VSV multiplication. Using antibodies neutralizing IFN-α/β, we show that the antiviral state induced by TSA is due to TSA-induced IFN production. The demonstration of the predominant role of histone deacetylation during the regulation of the constitutive repressed state of the IFN-β promoter constitutes an interesting advance on the understanding of the negative regulation of this gene and opens up the possibility of new therapeutic perspectives.

Inhibition of Histone Deacetylation: A Strategy for Tumor Radiosensitization

2007 ◽  
Vol 25 (26) ◽  
pp. 4051-4056 ◽  
Author(s):  
Kevin Camphausen ◽  
Philip J. Tofilon
Keyword(s):  
Histone Acetylation ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Human Tumor ◽  
Chemotherapeutic Agents ◽  
Histone Deacetylation ◽  
Hdac Activity ◽  
Two Parameters

Recently, strategies to enhance tumor radiosensitivity have begun to focus on targeting the molecules and processes that regulate cellular radioresponse. A molecular target that has begun to receive considerable attention is histone acetylation. Histone acetylation is determined by the dynamic interaction of two families of enzymes: histone acetylases and histone deacetylases (HDACs). Histone acetylation plays a role in regulating chromatin structure and gene expression—two parameters that have long been considered determinants of radioresponse. As a means of modifying histone acetylation status, considerable effort has been put into the development of inhibitors of HDAC activity. This has led to the generation of a relatively large number of structurally diverse compounds that can inhibit HDAC activity resulting in histone hyperacetylation. Many of the newer HDAC inhibitor compounds have been designed with better bioavailability or pharmacology than the first-generation compounds. Whereas a number of these second-generation HDAC inhibitors have antitumor activity in preclinical cancer models when delivered as single agents, early clinical data demonstrate only cytostasis when used as monotherapy. However, recent preclinical studies have indicated that HDAC inhibitors from structurally diverse classes can enhance both the in vitro and in vivo radiosensitivity of human tumor cell lines generated from a spectrum of solid tumors. HDAC inhibitors are in clinical trials as single modalities, in combination with chemotherapeutic agents, and recently, in combination with radiotherapy.

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