scholarly journals A New Member of the Sin3 Family of Corepressors Is Essential for Cell Viability and Required for Retroelement Propagation in Fission Yeast

1999 ◽  
Vol 19 (3) ◽  
pp. 2351-2365 ◽  
Author(s):  
Van Dinh Dang ◽  
Michael J. Benedik ◽  
Karl Ekwall ◽  
Jeannie Choi ◽  
Robin C. Allshire ◽  
...  
Keyword(s):  
Cell Viability ◽  
Fission Yeast ◽  
Histone Deacetylases ◽  
Immunofluorescence Microscopy ◽  
Trichostatin A ◽  
Critical Role ◽  
Predicted Amino Acid Sequence ◽  
Significant Similarity ◽  
Isolation And Characterization ◽  
Histone Deacetylase Inhibitor Trichostatin

ABSTRACT Tf1 is a long terminal repeat (LTR)-containing retrotransposon that propagates within the fission yeast Schizosaccharomyces pombe. LTR-retrotransposons possess significant similarity to retroviruses and therefore serve as retrovirus models. To determine what features of the host cell are important for the proliferation of this class of retroelements, we screened for mutations in host genes that reduced the transposition activity of Tf1. We report here the isolation and characterization of pst1 +, a gene required for Tf1 transposition. The predicted amino acid sequence of Pst1p possessed high sequence homology with the Sin3 family of proteins, known for their interaction with histone deacetylases. However, unlike the SIN3 gene of Saccharomyces cerevisiae, pst1 + is essential for cell viability. Immunofluorescence microscopy indicated that Pst1p was localized in the nucleus. Consistent with the critical role previously reported for Sin3 proteins in the histone acetylation process, we found that the growth of the strain with thepst1-1 allele was supersensitive to the specific histone deacetylase inhibitor trichostatin A. However, our analysis of strains with the pst1-1 mutation was unable to detect any changes in the acetylation of specific lysines of histones H3 and H4 as measured in bulk chromatin. Interestingly, the pst1-1mutant strain produced wild-type levels of Tf1-encoded proteins and cDNA, indicating that the defect in transposition occurred after reverse transcription. The results of immunofluorescence microscopy showed that the nuclear localization of the Tf1 capsid protein was disrupted in the strain with the pst1-1mutation, indicating an important role of pst1 +in modulating the nuclear import of Tf1 virus-like particles.

scholarly journals Histone Deacetylase Inhibitor Trichostatin A Reduces Endothelial Cell Proliferation by Suppressing STAT5A-Related Gene Transcription

2021 ◽  
Vol 11 ◽  
Author(s):  
Yize Li ◽  
Yongmei Zhao ◽  
Hongyan Peng ◽  
Jing Zhang ◽  
Lun Bo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Umbilical Vein ◽  
Endothelial Cell Proliferation ◽  
Molecular Events ◽  
Deacetylase Inhibitor ◽  
Histone Deacetylase Inhibitor Trichostatin ◽  
Umbilical Vein Endothelial Cells

Inhibitors of histone deacetylases (HDACi) have shown promising effects in preclinical applications for the treatment of many diseases. Confusedly though, the effects of the HDACi trichostatin A (TSA) on angiogenesis are variable among different diseases. This study investigated the direct effects of TSA on endothelial cells, which plays essential roles in angiogenesis and the underlying molecular events. TSA reduced the viability of human umbilical vein endothelial cells (HUVECs), in which proliferation-related genes including BIRC5, CKS1B, and NDC80 were found to be involved. Furthermore, signal transducer and activator of transcription 5 A (STAT5A) was demonstrated to be reduced by TSA and to mediate TSA-induced downregulation of BIRC5, CKS1B, and NDC80 and HUVEC proliferation. Mechanistically, data showed that STAT5A directly bound to the promoters of BIRC5, CKS1B, and NDC80 and activated their transcription through special DNA sequence sites. Finally, the TSA–STAT5A–BIRC5, CKS1B, and NDC80 axis also worked in a cancerous endothelial cell angiogenesis model. The results of this study revealed novel mechanisms underlying the effects of TSA on endothelial cells and provided insights for angiogenesis-associated diseases.

scholarly journals Coordinated Recruitment of Histone Methyltransferase G9a and Other Chromatin-Modifying Enzymes in SHP-Mediated Regulation of Hepatic Bile Acid Metabolism

2006 ◽  
Vol 27 (4) ◽  
pp. 1407-1424 ◽  
Author(s):  
Sungsoon Fang ◽  
Ji Miao ◽  
Lingjin Xiang ◽  
Bhaskar Ponugoti ◽  
Eckardt Treuter ◽  
...  
Keyword(s):  
Bile Acid ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Critical Role ◽  
Histone Methyltransferase ◽  
Bile Acid Metabolism ◽  
Dependent Manner ◽  
H3k9 Methylation ◽  
Hepatic Bile

ABSTRACT SHP has been implicated as a pleiotropic regulator of diverse biological functions by its ability to inhibit numerous nuclear receptors. Recently, we reported that SHP inhibits transcription of CYP7A1, a key gene in bile acid biosynthesis, by recruiting histone deacetylases (HDACs) and a Swi/Snf-Brm complex. To further delineate the mechanism of this inhibition, we have examined whether methylation of histones is also involved and whether a functional interplay between chromatin-modifying enzymes occurs. The histone methyltransferase G9a, but not SUV39, was colocalized with SHP in the nucleus and directly interacted with SHP in vitro. G9a, which was coimmunoprecipitated with hepatic SHP, methylated Lys-9 of histone 3 (H3K9) in vitro. Expression of G9a enhanced inhibition of CYP7A1 transcription by SHP, while a catalytically inactive G9a dominant negative (DN) mutant reversed the SHP inhibition. G9a was recruited to and H3K9 was methylated at the CYP7A1 promoter in a SHP-dependent manner in bile acid-treated HepG2 cells. Expression of the G9a-DN mutant inhibited H3K9 methylation, blocked the recruitment of the Brm complex, and partially reversed CYP7A1 inhibition by bile acids. Inhibition of HDAC activity with trichostatin A blocked deacetylation and methylation of H3K9 at the promoter, and, conversely, inhibition of H3K9 methylation by G9a-DN partially blocked deacetylation. Hepatic expression of G9a-DN in mice fed cholic acid disrupted bile acid homeostasis, resulting in increased bile acid pools and partial de-repression of Cyp7a1 and Cyp8b1. Our studies establish a critical role for G9a methyltransferase, histone deacetylases, and the Swi/Snf-Brm complex in the SHP-mediated inhibition of hepatic bile acid synthesis via coordinated chromatin modification at target genes.

scholarly journals Histone Deacetylase Homologs Regulate Epigenetic Inheritance of Transcriptional Silencing and Chromosome Segregation in Fission Yeast

Genetics ◽  
1998 ◽  
Vol 150 (2) ◽  
pp. 563-576 ◽  
Author(s):  
Shiv I S Grewal ◽  
Michael J Bonaduce ◽  
Amar J S Klar
Keyword(s):  
Fission Yeast ◽  
Histone Deacetylase ◽  
Chromosome Segregation ◽  
Histone Deacetylases ◽  
Essential Gene ◽  
Trichostatin A ◽  
Position Effect ◽  
Epigenetic Inheritance ◽  
Histone Deacetylation ◽  
Mat Locus

Abstract Position-effect control at the silent mat2-mat3 interval and at centromeres and telomeres in fission yeast is suggested to be mediated through the assembly of heterochromatin-like structures. Therefore, trans-acting genes that affect silencing may encode either chromatin proteins, factors that modify them, or factors that affect chromatin assembly. Here, we report the identification of an essential gene, clr6 (c ryptic loci r egulator), which encodes a putative histone deacetylase that when mutated affects epigenetically maintained repression at the mat2-mat3 region and at centromeres and reduces the fidelity of chromosome segregation. Furthermore, we show that the Clr3 protein, when mutated, alleviates recombination block at mat region as well as silencing at donor loci and at centromeres and telomeres, also shares strong homology to known histone deacetylases. Genetic analyses indicate that silencing might be regulated by at least two overlapping histone deacetylase activities. We also found that transient inhibition of histone deacetylase activity by trichostatin A results in the increased missegregation of chromosomes in subsequent generations and, remarkably, alters the imprint at the mat locus, causing the heritable conversion of the repressed epigenetic state to the expressed state. This work supports the model that the level of histone deacetylation has a role in the assembly of repressive heterochromatin and provides insight into the mechanism of epigenetic inheritance.

scholarly journals Epigenetic modulation of selected immune response genes and altered functions of T lymphocytes and macrophages collectively contribute to autoimmune diabetes protection

2021 ◽  
Author(s):  
Sundararajan Jayaraman ◽  
Maria Arianas ◽  
Arathi Jayaraman
Keyword(s):  
T Lymphocytes ◽  
Histone Deacetylases ◽  
Autoimmune Diabetes ◽  
Trichostatin A ◽  
Nod Mice ◽  
Copy Numbers ◽  
Deacetylase Inhibitor ◽  
Histone Deacetylase Inhibitor Trichostatin ◽  
Activated T Lymphocytes ◽  
Epigenetic Modulation

We have previously demonstrated that treatment of female NOD mice with the histone deacetylase inhibitor Trichostatin A (TSA) bestowed irreversible protection against diabetes. Herein we show that drug treatment diminished the infiltration of the pancreas with CD4+ and CD8+ T cells and Ly-6C+ monocytes. Significantly, TSA administration selectively repressed the expression of a set of genes exaggerated during diabetes and constitutively expressed primarily in the spleen and rarely in the pancreas. These genes encode lymphokines, macrophage-associated determinants, and transcription factors. Although the copy numbers of many histone deacetylases increased during diabetes in the spleen and pancreas, only those upregulated in the spleen were rendered sensitive to repression by TSA treatment. The T lymphocytes derived from drug-treated donors displayed diminished diabetogenic potential following transfer into immunodeficient NOD.scid mice. In the immunocompromised recipients, diabetes caused by the transfer of activated T lymphocytes from untreated diabetic mice was hampered by the co-transfer of highly purified splenic Ly-6C+ macrophages from drug-treated mice. However, the transfer of Ly-6C+ macrophages from drug-treated mice failed to block ongoing diabetes in wild-type NOD mice. These data demonstrate that the modified gene expression and functional alteration of T lymphocytes and macrophages collectively contribute to diabetes protection afforded by the histone modifier in female NOD mice.

scholarly journals A Novel Protein with Similarities to Rb Binding Protein 2 Compensates for Loss of Chk1 Function and Affects Histone Modification in Fission Yeast

2004 ◽  
Vol 24 (9) ◽  
pp. 3660-3669 ◽  
Author(s):  
Shakil Ahmed ◽  
Carmela Palermo ◽  
Shanhong Wan ◽  
Nancy C. Walworth
Keyword(s):  
Dna Damage ◽  
Fission Yeast ◽  
Histone Deacetylases ◽  
Cellular Response ◽  
Cell Cycle Progression ◽  
Trichostatin A ◽  
Fold Increase ◽  
Cycle Progression ◽  
Dna Damaging Agents ◽  
Mammalian Protein

ABSTRACT The conserved protein kinase Chk1 mediates cell cycle progression and consequently the ability of cells to survive when exposed to DNA damaging agents. Cells deficient in Chk1 are hypersensitive to such agents and enter mitosis in the presence of damaged DNA, whereas checkpoint-proficient cells delay mitotic entry to permit time for DNA repair. In a search for proteins that can improve the survival of Chk1-deficient cells exposed to DNA damage, we identified fission yeast Msc1, which is homologous to a mammalian protein that binds to the tumor suppressor Rb (RBP2). Msc1 and RBP2 each possess three PHD fingers, domains commonly found in proteins that influence the structure of chromatin. Msc1 is chromatin associated and coprecipitates a histone deacetylase activity, a property that requires the PHD fingers. Cells lacking Msc1 have a dramatically altered histone acetylation pattern, exhibit a 20-fold increase in global acetylation of histone H3 tails, and are readily killed by trichostatin A, an inhibitor of histone deacetylases. We postulate that Msc1 plays an important role in regulating chromatin structure and that this function modulates the cellular response to DNA damage.

scholarly journals Isolation and characterization of the fission yeast protein phosphatase gene ppe1+ involved in cell shape control and mitosis.

1993 ◽  
Vol 4 (3) ◽  
pp. 303-313 ◽  
Author(s):  
M Shimanuki ◽  
N Kinoshita ◽  
H Ohkura ◽  
T Yoshida ◽  
T Toda ◽  
...  
Keyword(s):  
Fission Yeast ◽  
Shape Control ◽  
Budding Yeast ◽  
Suppressor Gene ◽  
Predicted Amino Acid Sequence ◽  
Permissive Temperature ◽  
Multicopy Suppressor ◽  
Isolation And Characterization ◽  
Cold Sensitive ◽  
Cell Shape Control

We isolated a fission yeast putative protein serine/threonine phosphatase gene designated ppe1+ by hybridization. The predicted amino acid sequence is similar to those of the fission yeast ppa2 (53% identity) and dis2 (39%) phosphatases, and highly similar to those of the budding yeast SIT4 (72%), Drosophila PPV (68%) and rabbit PPX (61%) phosphatases. Antibodies against ppe1 protein identified a 37-kd polypeptide in fission yeast. A gene disruption (designated delta ppe1) caused cold-sensitive lethality and short, pear-shaped cells. These phenotypes were fully suppressed by a plasmid carrying ppe1+. Three classes of multicopy suppressor genes for delta ppe1 were identified as follows: 1) ppa1+ and ppa2+ encoding type 2A-like phosphatases, 2) mitotically essential dis3+ similar to the budding yeast SSD1/SRK1, a suppressor for sit4, and 3) pck1+ coding for a protein kinase C-like kinase. Consistently, the budding yeast SIT4 gene was also a multicopy suppressor for delta ppe1. Phosphatase ppe1 may play a role in cell morphogenesis and mitosis by either regulating or being regulated by these multicopy suppressor gene products. Consistent with this hypothesis, double mutants ppe1-ppa2 and ppe1-pck1 are lethal at the permissive temperature.

scholarly journals Histone Deacetylase Inhibitor, Trichostatin A, Synergistically Enhances Paclitaxel-Induced Cytotoxicity in Urothelial Carcinoma Cells by Suppressing the ERK Pathway

2019 ◽  
Vol 20 (5) ◽  
pp. 1162 ◽  
Author(s):  
Fu-Shun Hsu ◽  
June-Tai Wu ◽  
Jing-Yi Lin ◽  
Shao-Ping Yang ◽  
Kuan-Lin Kuo ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Erk Pathway ◽  
Antitumor Effects ◽  
Nude Mouse Model ◽  
Synergistic Cytotoxicity ◽  
Histone Deacetylase Inhibitor Trichostatin

Trichostatin A (TSA), an antifungal antibiotic derived from Streptomyces, inhibits mammalian histone deacetylases, and especially, selectively inhibits class I and II histone deacetylase (HDAC) families of enzymes. TSA reportedly elicits an antiproliferative response in multifarious tumors. This study investigated the antitumor effects of TSA alone and in combination with paclitaxel when applied to two high-grade urothelial carcinoma (UC) cell lines (BFTC-905 and BFTC-909). Fluorescence-activated cell sorting, flow cytometry, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium assay were used to assess TSA’s cytotoxicity and effects on apoptosis induction. TSA induced synergistic cytotoxicity, when combined with paclitaxel (combination index < 1), resulted in concomitant suppression of paclitaxel-induced activation of phospho-extracellular signal-regulated kinase (ERK) 1/2. A xenograft nude mouse model confirmed that TSA enhances the antitumor effects of paclitaxel. These findings demonstrate that the administration of TSA in combination with paclitaxel elicits a synergistic cytotoxic response. The results of this study indicate that the chemoresistance of UC could be circumvented by combining HDAC inhibitors to target the ERK pathway.

scholarly journals Histone Deacetylase Inhibitor Trichostatin A Ameliorated Endotoxin-Induced Neuroinflammation and Cognitive Dysfunction

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Chung-Hsi Hsing ◽  
Shih-Kai Hung ◽  
Yeong-Chang Chen ◽  
Tsui-Shan Wei ◽  
Ding-Ping Sun ◽  
...  
Keyword(s):  
Weight Loss ◽  
Cognitive Function ◽  
Cognitive Dysfunction ◽  
Histone Deacetylases ◽  
Inflammatory Responses ◽  
Social Withdrawal ◽  
Trichostatin A ◽  
Body Weight Loss ◽  
Microglial Cells ◽  
Histone Deacetylase Inhibitor Trichostatin

Excessive production of cytokines by microglia may cause cognitive dysfunction and long-lasting behavioral changes. Activating the peripheral innate immune system stimulates cytokine secretion in the central nervous system, which modulates cognitive function. Histone deacetylases (HDACs) modulate cytokine synthesis and release. Trichostatin A (TSA), an HDAC inhibitor, is documented to be anti-inflammatory and neuroprotective. We investigated whether TSA reduces lipopolysaccharide- (LPS-) induced neuroinflammation and cognitive dysfunction. ICR mice were first intraperitoneally (i.p.) injected with vehicle or TSA (0.3 mg/kg). One hour later, they were injected (i.p.) with saline orEscherichia coliLPS (1 mg/kg). We analyzed the food and water intake, body weight loss, and sucrose preference of the injected mice and then determined the microglia activation and inflammatory cytokine expression in the brains of LPS-treated mice and LPS-treated BV-2 microglial cells. In the TSA-pretreated mice, microglial activation was lower, anhedonia did not occur, and LPS-induced cognitive dysfunction (anorexia, weight loss, and social withdrawal) was attenuated. Moreover, mRNA expression of HDAC2, HDAC5, indoleamine 2,3-dioxygenase (IDO), TNF-α, MCP-1, and IL-1βin the brain of LPS-challenged mice and in the LPS-treated BV-2 microglial cells was lower. TSA diminished LPS-induced inflammatory responses in the mouse brain and modulated the cytokine-associated changes in cognitive function, which might be specifically related to reducing HDAC2 and HDAC5 expression.

scholarly journals Histone Deacetylation of RB-Responsive Promoters: Requisite for Specific Gene Repression but Dispensable for Cell Cycle Inhibition

2003 ◽  
Vol 23 (21) ◽  
pp. 7719-7731 ◽  
Author(s):  
Hasan Siddiqui ◽  
David A. Solomon ◽  
Ranjaka W. Gunawardena ◽  
Ying Wang ◽  
Erik S. Knudsen
Keyword(s):  
Cell Cycle ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Cellular Proliferation ◽  
Trichostatin A ◽  
Critical Role ◽  
Histone Deacetylation ◽  
Specific Gene ◽  
Specific Subset ◽  
Cell Cycle Inhibition

ABSTRACT The retinoblastoma tumor suppressor protein (RB) is targeted for inactivation in the majority of human tumors, underscoring its critical role in attenuating cellular proliferation. RB inhibits proliferation by repressing the transcription of genes that are essential for cell cycle progression. To repress transcription, RB assembles multiprotein complexes containing chromatin-modifying enzymes, including histone deacetylases (HDACs). However, the extent to which HDACs participate in transcriptional repression and are required for RB-mediated repression has not been established. Here, we investigated the role of HDACs in RB-dependent cell cycle inhibition and transcriptional repression. We find that active RB mediates histone deacetylation on cyclin A, Cdc2, topoisomerase IIα, and thymidylate synthase promoters. We also demonstrate that this deacetylation is HDAC dependent, since the HDAC inhibitor trichostatin A (TSA) prevented histone deacetylation at each promoter. However, TSA treatment blocked RB repression of only a specific subset of genes, thereby demonstrating that the requirement of HDACs for RB-mediated transcriptional repression is promoter specific. The HDAC-independent repression was not associated with DNA methylation or gene silencing but was readily reversible. We show that this form of repression resulted in altered chromatin structure and was dependent on SWI/SNF chromatin remodeling activity. Importantly, we find that cell cycle inhibitory action of RB is not intrinsically dependent on the ability to recruit HDAC activity. Thus, while HDACs do play a major role in RB-mediated repression, they are dispensable for the repression of critical targets leading to cell cycle arrest.

Sign in / Sign up

Export Citation Format

Share Document