scholarly journals Histone Deacetylases (HDACs): Evolution, Specificity, Role in Transcriptional Complexes, and Pharmacological Actionability

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 556 ◽  
Author(s):  
Giorgio Milazzo ◽  
Daniele Mercatelli ◽  
Giulia Di Muzio ◽  
Luca Triboli ◽  
Piergiuseppe De Rosa ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Histone Deacetylases ◽  
Expression Profiles ◽  
Hdac Inhibitors ◽  
Gene Expression Profiles ◽  
Chromatin Binding ◽  
Human Interactome ◽  
Anti Cancer ◽  
Functional Consequences

Histone deacetylases (HDACs) are evolutionary conserved enzymes which operate by removing acetyl groups from histones and other protein regulatory factors, with functional consequences on chromatin remodeling and gene expression profiles. We provide here a review on the recent knowledge accrued on the zinc-dependent HDAC protein family across different species, tissues, and human pathologies, specifically focusing on the role of HDAC inhibitors as anti-cancer agents. We will investigate the chemical specificity of different HDACs and discuss their role in the human interactome as members of chromatin-binding and regulatory complexes.

scholarly journals Systematic polypharmacology and drug repurposing via an integrated L1000-based Connectivity Map database mining

2018 ◽  
Vol 5 (11) ◽  
pp. 181321 ◽  
Author(s):  
Tsang-Pai Liu ◽  
Yao-Yu Hsieh ◽  
Chia-Jung Chou ◽  
Pei-Ming Yang
Keyword(s):  
Large Scale ◽  
Human Cancer ◽  
Expression Profiles ◽  
Hdac Inhibitors ◽  
Gene Expression Profiles ◽  
Drug Repurposing ◽  
Connectivity Map ◽  
Human Cancer Cells ◽  
Experimental Drugs ◽  
Anti Cancer

Drug repurposing aims to find novel indications of clinically used or experimental drugs. Because drug data already exist, drug repurposing may save time and cost, and bypass safety concerns. Polypharmacology, one drug with multiple targets, serves as a basis for drug repurposing. Large-scale databases have been accumulated in recent years, and utilization and integration of these databases would be highly helpful for polypharmacology and drug repurposing. The Connectivity Map (CMap) is a database collecting gene-expression profiles of drug-treated human cancer cells, which has been widely used for investigation of polypharmacology and drug repurposing. In this study, we integrated the next-generation L1000-based CMap and an analytic Web tool, the L1000FWD, for systematic analyses of polypharmacology and drug repurposing. Two different types of anti-cancer drugs were used as proof-of-concept examples, including histone deacetylase (HDAC) inhibitors and topoisomerase inhibitors. We identified KM-00927 and BRD-K75081836 as novel HDAC inhibitors and mitomycin C as a topoisomerase IIB inhibitor. Our study provides a prime example of utilization and integration of the freely available public resources for systematic polypharmacology analysis and drug repurposing.

scholarly journals A Cell-Based Platform for the Investigation of Immunoproteasome Subunit β5i Expression and Biology of β5i-Containing Proteasomes

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3049
Author(s):  
Alexander Burov ◽  
Sergei Funikov ◽  
Elmira Vagapova ◽  
Alexandra Dalina ◽  
Alexander Rezvykh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Large Scale ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Tnf Α ◽  
Anti Cancer ◽  
A Cell ◽  
Established Cell

The degradation of most intracellular proteins is a dynamic and tightly regulated process performed by proteasomes. To date, different forms of proteasomes have been identified. Currently the role of non-constitutive proteasomes (immunoproteasomes (iPs) and intermediate proteasomes (intPs)) has attracted special attention. Here, using a CRISPR-Cas9 nickase technology, four cell lines: histiocytic lymphoma, colorectal adenocarcinoma, cervix adenocarcinoma, and hepatocarcinoma were modified to express proteasomes with mCherry-tagged β5i subunit, which is a catalytic subunit of iPs and intPs. Importantly, the expression of the chimeric gene in modified cells is under the control of endogenous regulatory mechanisms and is increased following IFN-γ and/or TNF-α stimulation. Fluorescent proteasomes retain catalytic activity and are distributed within the nucleus and cytoplasm. RNAseq reveals marginal differences in gene expression profiles between the modified and wild-type cell lines. Predominant metabolic pathways and patterns of expressed receptors were identified for each cell line. Using established cell lines, we demonstrated that anti-cancer drugs Ruxolitinib, Vincristine and Gefitinib stimulated the expression of β5i-containing proteasomes, which might affect disease prognosis. Taken together, obtained cell lines can be used as a platform for real-time studies of immunoproteasome gene expression, localization of iPs and intPs, interaction of non-constitutive proteasomes with other proteins, proteasome trafficking and many other aspects of proteasome biology in living cells. Moreover, the established platform might be especially useful for fast and large-scale experiments intended to evaluate the effects of different conditions including treatment with various drugs and compounds on the proteasome pool.

scholarly journals Fusarium verticillioides FvPex8 is a key component of peroxisomal docking/translocation module that serves important roles in fumonisin biosynthesis but not in virulence

2020 ◽  
Author(s):  
Wenying Yu ◽  
Mei Lin ◽  
Minghui Peng ◽  
Huijuan Yan ◽  
Jie Zhou ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Fusarium Verticillioides ◽  
Fumonisin B1 ◽  
Gene Expression Profiles ◽  
Deletion Mutants ◽  
Altered Expression ◽  
The Core ◽  
Metabolic Functions ◽  
Peroxisome Membrane

AbstractPeroxisomes are ubiquitous organelles in eukaryotic cells that fulfill various important metabolic functions. In this study, we investigated the role of Docking/Translocation Module (DTM) peroxins, mainly FvPex8, FvPex13, FvPex14, and FvPex33, in Fusarium verticillioides virulence and fumonisin B1 (FB1) biosynthesis. Protein interaction experiments suggested that FvPex13 serves as the core subunit of F. verticillioides DTM. When we generated gene deletion mutants (ΔFvpex8, ΔFvpex13, ΔFvpex14, ΔFvpex33, ΔFvpex33/14) and examined whether the expression of other peroxin genes were affected in the DTM mutants, ΔFvpex8 strain showed most drastic changes to PEX gene expression profiles. Deletion mutants exhibited disparity in carbon source utilization and defect in cell wall integrity when stress agents were applied. Under nutrient starvation, mutants also showed higher levels of lipid droplet accumulation. Notably, ΔFvpex8 mutant showed significant FB1 reduction and altered expression of FUM1 and FUM19 genes. However, FvPex13 was primarily responsible for virulence, while ΔFvpex33/14 double mutant also showed virulence defect. In summary, our study suggests that FvPex13 is the core component of DTM, regulating peroxisome membrane biogenesis as well as PTS1- and PTS2-mediated transmembrane cargo transportation. Importantly, we predict FvPex8 as a key component in DTM that affects peroxisome function in FB1 biosynthesis in F. verticillioides.

scholarly journals Characterization of Genes Associated with TGA7 During the Floral Transition

2020 ◽  
Author(s):  
Xiaorui Xu ◽  
Jingya Xu ◽  
Chen Yuan ◽  
Yikai Hu ◽  
Qinggang Liu ◽  
...  
Keyword(s):  
Flowering Time ◽  
Expression Profiles ◽  
Plant Defence ◽  
Gene Expression Profiles ◽  
Floral Transition ◽  
Cdna Libraries ◽  
Genetic Pathways ◽  
Time Control ◽  
Pathways Analysis

Abstract BackgroundThe TGA family has ten members and plays vital roles in plant defence and development in Arabidopsis. However, involvement of TGAs in control of flowering time remains largely unknown and requires further investigation. ResultsTo study the role of TGA7 during the floral transition, we first tested phenotypes of tga7 mutant, which displayed delay-flowering phenotype under both long-day and short-day conditions. We then performed flowering genetic pathways analysis and found that both autonomous and thermosensory pathways may affect TGA7 expression. Furthermore, to reveal differential gene expression profiles between wild-type (WT) and tga7, cDNA libraries were generated for WT and tga7 mutant seedlings at 9 DAG (days after germination). For each library, deep-sequencing produced approximately 6.67 Gb of high-quality sequences with the majority (84.55%) of mRNAs between 500 and 3000 nucleotides in length. Three hundred and twenty-five differentially expressed genes (DEGs) were identified between WT and tga7 mutant seedlings. Among them, four genes are associated with flowering time control. Differential expression of the four flowering-related DEGs was further validated by qRT-PCR.ConclusionsTransciptomic sequencing coupled with flowering genetic pathways analysis provides a framework for further studying the role of TGA7 in promoting flowering.

scholarly journals Comparative Integrated Omics Analysis of the Hfq Regulon in Bordetella pertussis

2019 ◽  
Vol 20 (12) ◽  
pp. 3073 ◽  
Author(s):  
Ana Dienstbier ◽  
Fabian Amman ◽  
Daniel Štipl ◽  
Denisa Petráčková ◽  
Branislav Večerek
Keyword(s):  
Gene Expression ◽  
Bordetella Pertussis ◽  
Transcriptional Control ◽  
Whooping Cough ◽  
Expression Profiles ◽  
Bacterial Pathogen ◽  
Gene Expression Profiles ◽  
Control Of Gene Expression ◽  
Proteomic Data

Bordetella pertussis is a Gram-negative strictly human pathogen of the respiratory tract and the etiological agent of whooping cough (pertussis). Previously, we have shown that RNA chaperone Hfq is required for virulence of B. pertussis. Furthermore, microarray analysis revealed that a large number of genes are affected by the lack of Hfq. This study represents the first attempt to characterize the Hfq regulon in bacterial pathogen using an integrative omics approach. Gene expression profiles were analyzed by RNA-seq and protein amounts in cell-associated and cell-free fractions were determined by LC-MS/MS technique. Comparative analysis of transcriptomic and proteomic data revealed solid correlation (r2 = 0.4) considering the role of Hfq in post-transcriptional control of gene expression. Importantly, our study confirms and further enlightens the role of Hfq in pathogenicity of B. pertussis as it shows that Δhfq strain displays strongly impaired secretion of substrates of Type III secretion system (T3SS) and substantially reduced resistance to serum killing. On the other hand, significantly increased production of proteins implicated in transport of important metabolites and essential nutrients observed in the mutant seems to compensate for the physiological defect introduced by the deletion of the hfq gene.

Repurposing natural products as novel HDAC inhibitors by comparative analysis of gene expression profiles

Phytomedicine ◽  
2019 ◽  
Vol 59 ◽  
pp. 152900 ◽  
Author(s):  
Mi Ran Byun ◽  
Dae Hoon Lee ◽  
Young Pyo Jang ◽  
Ho Sub Lee ◽  
Jin Woo Choi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Natural Products ◽  
Comparative Analysis ◽  
Expression Profiles ◽  
Hdac Inhibitors ◽  
Gene Expression Profiles

scholarly journals THE ROLE OF TRANSCRIPTOMICS: PHYSIOLOGICAL EQUIVALENCE BASED ON GENE EXPRESSION PROFILES

2017 ◽  
Vol 5 (0) ◽  
pp. 21-35 ◽  
Author(s):  
Shiori Miura ◽  
Takehiro Himaki ◽  
Junko Takahashi ◽  
Hitoshi Iwahashi
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Gene Expression Profiles

scholarly journals Image-based drug screen identifies HDAC inhibitors as novel Golgi disruptors synergizing with JQ1

2017 ◽  
Vol 28 (26) ◽  
pp. 3756-3772 ◽  
Author(s):  
Mathieu Gendarme ◽  
Jan Baumann ◽  
Tatiana I. Ignashkova ◽  
Ralph K. Lindemann ◽  
Jan H. Reiling
Keyword(s):  
Small Molecules ◽  
Expression Profiles ◽  
Hdac Inhibitors ◽  
Gene Expression Profiles ◽  
Brefeldin A ◽  
Hdac Inhibition ◽  
Drug Induced ◽  
Dna Damaging Agents ◽  
Phenotypic Screen ◽  
Golgi Structure

The Golgi apparatus is increasingly recognized as a major hub for cellular signaling and is involved in numerous pathologies, including neurodegenerative diseases and cancer. The study of Golgi stress-induced signaling pathways relies on the selectivity of the available tool compounds of which currently only a few are known. To discover novel Golgi-fragmenting agents, transcriptomic profiles of cells treated with brefeldin A, golgicide A, or monensin were generated and compared with a database of gene expression profiles from cells treated with other bioactive small molecules. In parallel, a phenotypic screen was performed for compounds that alter normal Golgi structure. Histone deacetylase (HDAC) inhibitors and DNA-damaging agents were identified as novel Golgi disruptors. Further analysis identified HDAC1/HDAC9 as well as BRD8 and DNA-PK as important regulators of Golgi breakdown mediated by HDAC inhibition. We provide evidence that combinatorial HDACi/(+)-JQ1 treatment spurs synergistic Golgi dispersal in several cancer cell lines, pinpointing a possible link between drug-induced toxicity and Golgi morphology alterations.

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