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Changes in histone code Regulation during the Initiation of Paraptosis-Like Death of HEp-2 Tumor Cells by Oxidized Disulfiram Derivatives

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BIOCHEMISTRY MOSCOW SUPPLEMENT SERIES A-MEMBRANE AND CELL BIOLOGY 2024年第2期18卷 78-89页

作者： Solovieva, M. E. Shatalin, Yu. V. Akatov, V. S. Russian Acad Sci Inst Theoret & Expt Biophys Pushchino 142290 Russia

Disulfiram (DSF) and its oxidized derivatives (DSFoxy) are currently being investigated as potential anticancer agents. We previously found that DSFoxy initiate the paraptosis-like death of tumor cells, which is of potential interest for the treatment of tumors resistant to the initiation of apoptosis. Based on bioinformatics analysis of mass spectrometric data on protein ubiquitination, we formulated a conception about the important role of disruption of the retrograde transport of damaged proteins from the endoplasmic reticulum to the cytosol in the mechanism of initiation of paraptosis-like cell death. In the present work, it has been found that DSFoxy, in the process of initiating paraptosis-like death of human adenocarcinoma HEp-2 cells, also enhances the ubiquitination of histones and histone code enzymes. In particular, this applies to the ubiquitination of histone H2BC12, histone methyltransferases responsible for transcription and repair of damaged DNA, as well as acetylating and ubiquitin-conjugating proteins. Bioinformatics analysis of changes in ubiquitination of cell nuclear proteins using the STRING database revealed during this process an increase in the occurrence of ubiquitinated proteins (functional enrichment) of cell cycle regulation, cell response to DNA damage and DNA repair, the regulation of which also depends on the histone code. This directly indicates damage to the cell nucleus and is consistent with confocal microscopy data. These results indicate that paraptosis-like death initiated by DSFoxy is accompanied, along with impairment of retrograde transport and ER stress, also by a change in regulation of the histone code, which points to a pleiotropic mechanism of cell death induction.

关键词： histone code histones histone ubiquitination histone methylation paraptosis disulfiram

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A Dynamic and Combinatorial histone code Drives Malaria Parasite Asexual and Sexual Development

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MOLECULAR & CELLULAR PROTEOMICS 2022年第3期21卷 100199页

作者： von Gruning, Hilde Coradin, Mariel Mendoza, Mariel R. Reader, Janette Sidoli, Simone Garcia, Benjamin A. Birkholtz, Lyn-Marie Univ Pretoria Dept Biochem Genet & Microbiol Pretoria South Africa Univ Pretoria Inst Sustainable Malaria Control Pretoria South Africa Univ Penn Perelman Sch Med Epigenet Inst Dept Biochem & Biophys Philadelphia PA 19104 USA Albert Einstein Coll Med Dept Biochem Bronx NY 10467 USA Univ Colorado Dept Mol Cellular & Dev Biol Boulder CO 80309 USA

histone posttranslational modifications (PTMs) frequently co-occur on the same chromatin domains or even in the same molecule. It is now established that these "histone codes" are the result of cross talk between enzymes that catalyze multiple PTMs with univocal readout as compared with these PTMs in isolation. Here, we performed a comprehensive identification and quantification of histone codes of the malaria parasite, Plasmodium falciparum. We used advanced quantitative middle-down proteomics to identify combinations of PTMs in both the proliferative, asexual stages and transmissible, sexual gametocyte stages of P. falciparum. We provide an updated, high-resolution compendium of 77 PTMs on H3 and H3.3, of which 34 are newly identified in P. falciparum. Coexisting PTMs with unique stage distinctions were identified, indicating that many of these combinatorial PTMs are associated with specific stages of the parasite life cycle. We focused on the code H3R17me2K18acK23ac for its unique presence in mature gametocytes;chromatin proteomics identified a gametocyte-specific SAGA-like effector complex including the transcription factor AP2G2, which we tied to this specific histone code, as involved in regulating gene expression in mature gametocytes. Ultimately, this study unveils previously undiscovered histone PTMs and their functional relationship with coexisting partners. These results highlight that investigating chromatin regulation in the parasite using single histone PTM assays might overlook higher-order gene regulation for distinct proliferation and differentiation processes.

关键词： gametocyte histone code malaria middle-down mass spectrometry proteomics parasite Plasmodium falciparum posttranslational modification PTM

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Evidence for the implication of the histone code in building the genome structure

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BIOSYSTEMS 2018年 164卷 49-59页

作者： Prakash, Kirti Fournier, David CNRS Inst Curie Physicochim Curie UMR 168 F-75005 Paris France Oxford Nanoimaging Ltd Oxford OX1 1JD England Univ Oxford Dept Biochem Micron Adv Bioimaging Unit Oxford England Johannes Gutenberg Univ Mainz Fac Biol D-55128 Mainz Germany Johannes Gutenberg Univ Mainz Ctr Computat Sci D-55128 Mainz Germany

histones are punctuated with small chemical modifications that alter their interaction with DNA. One attractive hypothesis stipulates that certain combinations of these histone modifications may function, alone or together, as a part of a predictive histone code to provide ground rules for chromatin folding. We consider four features that relate histone modifications to chromatin folding: charge neutralisation, molecular specificity, robustness and evolvability. Next, we present evidence for the association among different histone modifications at various levels of chromatin organisation and show how these relationships relate to function such as transcription, replication and cell division. Finally, we propose a model where the histone code can set critical checkpoints for chromatin to fold reversibly between different orders of the organisation in response to a biological stimulus. (C) 2017 Elsevier B.V. All rights reserved.

关键词： DNA Nucleosomes histone modifications Chromatin domains Chromosomes histone code Chromatin folding Genome structure

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Beyond the histone code: A Physical Map of Chromatin States

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MOLECULAR CELL 2018年第1期69卷 5-7页

作者： Tchasovnikarova, Iva A. Kingston, Robert E. Massachusetts Gen Hosp Dept Mol Biol Boston MA 02114 USA Harvard Med Sch Dept Genet Boston MA 02114 USA

Post-translational modifications of histones are widely used to discriminate between different types of chromatin. In a recent issue of Molecular Cell, Becker et al. (2017) delineate chromatin states based on physical... 详细信息

关键词： histone code Physical map Chromatin histones

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Fluorogenic sensor platform for the histone code using receptors from dynamic combinatorial libraries

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CHEMICAL SCIENCE 2017年第2期8卷 1422-1428页

作者： Peacor, Brendan C. Ramsay, Christopher M. Waters, Marcey L. Univ North Carolina Chapel Hill Dept Chem CB 3290 Chapel Hill NC 27599 USA

Post-translational modifications (PTMs) on histone tails act in diverse combinations in the 'histone code' to control gene expression, with dysregulation observed in a variety of diseases. However, detection and sensing methods are limited, expensive, and/or low-throughput, including MS and antibody based detection. We found that by combining four synthetic receptors developed by dynamic combinatorial chemistry (DCC) in an indicator displacement system, we are able to create a pattern-based sensor platform that can discriminate single PTMs such as methylation and acetylation on a representative histone peptide with 100% accuracy as well as peptides bearing both dimethyl and trimethyl lysine in the presence of arginine methylation, which has not previously been demonstrated, and can even correctly distinguish the position of lysine methylation individually or in the presence of other PTMs. To extend this approach, a full panel of thirteen analytes containing different combinations of PTMs were classified with 96 +/- 1% overall accuracy in a 50% left-out analysis, demonstrating the robustness and versatility of the sensor array. Finally, the sensor platform was also used to demonstrate proof of concept for enzymatic assays by analysing the mock reaction of a threonine kinase, successfully identifying analytes representative of substrate conversion both with and without neighboring PTMs. This work provides a rapid platform for the analysis of peptides bearing complex modifications and highlights the utility of receptors discovered though DCC that display variations in binding affinity and selectivity.

关键词： Peptides enzymatic assay histone code Platform Combinatorial libraries Sensors Protein-Serine-Threonine Kinases histones DCC Genes Receptor Methylation

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Conservation and divergence of the histone code in nucleomorphs

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BIOLOGY DIRECT 2016年第1期11卷 18-18页

作者： Marinov, Georgi K. Lynch, Michael Indiana Univ Dept Biol Bloomington IN 47405 USA

Background: Nucleomorphs, the remnant nuclei of photosynthetic algae that have become endosymbionts to other eukaryotes, represent a unique example of convergent reductive genome evolution in eukaryotes, having evolved independently on two separate occasions in chlorarachniophytes and cryptophytes. The nucleomorphs of the two groups have evolved in a remarkably convergent manner, with numerous very similar features. Chief among them is the extreme reduction and compaction of nucleomorph genomes, with very small chromosomes and extremely short or even completely absent intergenic spaces. These characteristics pose a number of intriguing questions regarding the mechanisms of transcription and gene regulation in such a crowded genomic context, in particular in terms of the functioning of the histone code, which is common to almost all eukaryotes and plays a central role in chromatin biology. Results: This study examines the sequences of nucleomorph histone proteins in order to address these issues. Remarkably, all classical transcription-and repression-related components of the histone code seem to be missing from chlorarachniophyte nucleomorphs. Cryptophyte nucleomorph histones are generally more similar to the conventional eukaryotic state;however, they also display significant deviations from the typical histone code. Based on the analysis of specific components of the code, we discuss the state of chromatin and the transcriptional machinery in these nuclei. Conclusions: The results presented here shed new light on the mechanisms of nucleomorph transcription and gene regulation and provide a foundation for future studies of nucleomorph chromatin and transcriptional biology.

关键词： histones Nucleomorphs histone code Transcription Chromatin

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Modifications of RNA polymerase II CTD: Connections to the histone code and cellular function

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BIOTECHNOLOGY ADVANCES 2015年第6期33卷 856-872页

作者： Srivastava, Rakesh Ahn, Seong Hoon Hanyang Univ Coll Sci & Technol Div Mol & Life Sci Ansan 426791 Gyeonggi Do South Korea

At the onset of transcription, many protein machineries interpret the cellular signals that regulate gene expression. These complex signals are mostly transmitted to the indispensable primary proteins involved in transcription, RNA polymerase II (RNAPII) and histones. RNAPII and histones are so well coordinated in this cellular function that each cellular signal is precisely allocated to specific machinery depending on the stage of transcription. The carboxyterminal domain (CTD) of RNAPII in eukaryotes undergoes extensive posttranslational modification, called the 'CTD code', that is indispensable for coupling transcription with many cellular processes, including mRNA processing. The posttranslational modification of histones, known as the 'histone code', is also critical for gene transcription through the reversible and dynamic remodeling of chromatin structure. Notably, the histone code is closely linked with the LID code, and their combinatorial effects enable the delicate regulation of gene transcription. This review elucidates recent findings regarding the CTD modifications of RNAPII and their coordination with the histone code, providing integrative pathways for the fine-tuned regulation of gene expression and cellular function. (C) 2015 Elsevier Inc. All rights reserved.

关键词： RNA polymerase II histone Transcription Posttranslational modification histone code CID code

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Combined oral contraceptive synergistically activates mineralocorticoid receptor through histone code modifications

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EUROPEAN JOURNAL OF PHARMACOLOGY 2015年第0期769卷 48-54页

作者： Igunnu, Adedoyin Seok, Young-Mi Olatunji, Lawrence A. Kang, Seol-Hee Kim, Inkyeom Kyungpook Natl Univ Sch Med Dept Pharmacol Daegu 700842 South Korea Kyungpook Natl Univ Sch Med Cardiovasc Res Inst Daegu 700842 South Korea Kyungpook Natl Univ Sch Med Cell & Matrix Res Inst Daegu 700842 South Korea Kyungpook Natl Univ Sch Med Dept Biomed Sci Plus KNU Biomed Convergence Program BK21 Daegu 700842 South Korea Korea Promot Inst Tradit Med Ind Gyongsan 712260 Gyeongbuk South Korea

Clinical studies have shown that the use of combined oral contraceptive in pre-menopausal women is associated with fluid retention. However, the molecular mechanism is still elusive. We hypothesized that combined oral contraceptive (COC) ethinyl estradiol (EE) and norgestrel (N) synergistically activates mineralocorticoid receptor (MR) through histone code modifications. Twelve-week-old female SpragueDawley rats were treated with olive oil (control), a combination of 0.1 ng EE and 1.0 mu g N (low COC) or 1.0 mu g EE and 10.0 mu g N (high COC) as well as 0.1 or 1.0 mu g EE and 1.0 or 10.0 mu g N daily for 6 weeks. Expression of MR target genes in kidney cortex was determined by quantitative real-time polymerase chain reaction. MR was quantified by western blot. Recruitment of MR and RNA polymerase II (Pol II) on promoters of target genes as well as histone code modifications was analyzed by chromatin immunoprecipitation assay. Treatment with COC increased renal cortical expression of MR target genes such as serum and glucocorticoid-regulated kinase 1 (Sgk-1), glucocorticoid-induced leucine zipper (Gilz), epithelial Na-' channel (Enac) and Na+-K+-ATPase subunit al (Atp1a1). Although COC increased neither serum aldosterone nor MR expression in kidney cortex, it increased recruitment of MR and Pol II in parallel with increased H3Ac and H3K4me3 on the promoter regions of MR target genes. However, treatment with EE or N alone did not affect renal cortical expression of Sgk-1, Gilz, Enac or Atp1a1. These results indicate that COC synergistically activates MR through histone code modifications. (C) 2015 Elsevier B.V. All rights reserved.

关键词： Oral contraceptive Mineralocorticoid receptor histone code Gene transcription

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Synthetic histone code

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CURRENT OPINION IN CHEMICAL BIOLOGY 2015年第0期28卷 131-140页

作者： Fischle, Wolfgang Mootz, Henning D. Schwarzer, Dirk Max Planck Inst Biophys Chem D-37077 Gottingen Germany Univ Munster Inst Biochem D-48149 Munster Germany Univ Tubingen Interfac Inst Biochem D-72076 Tubingen Germany

Chromatin is the universal template of genetic information in all eukaryotic cells. This complex of DNA and histone proteins not only packages and organizes genomes but also regulates gene expression. A multitude of posttranslational histone modifications and their combinations are thought to constitute a code for directing distinct structural and functional states of chromatin. Methods of protein chemistry, including protein semisynthesis, amber suppression technology, and cysteine bioconjugation, have enabled the generation of so-called designer chromatin containing histones in defined and homogeneous modification states. Several of these approaches have matured from proof-of-concept studies into efficient tools and technologies for studying the biochemistry of chromatin regulation and for interrogating the histone code. We summarize pioneering experiments and recent developments in this exciting field of chemical biology.

关键词： efficient tools histone code codes Genome genetic information histones Technology Chromatin

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histone code of genes induced by co-treatment with a glucocorticoid hormone agonist and a p44/42 MAPK inhibitor in human small intestinal Caco-2 cells

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BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS 2014年第1期1840卷 693-700页

作者： Inamochi, Yuko Mochizuki, Kazuki Goda, Toshinao Univ Shizuoka Grad Sch Nutr & Environm Sci Lab Nutr Physiol Shizuoka 4228526 Japan Univ Shizuoka Global COE Shizuoka 4228526 Japan Univ Yamanashi Fac Life & Environm Sci Kofu Yamanashi Japan

Background: Inactivation of glucocorticoid hormones and p44/42 mitogen-activated protein kinase (MAPK) is thought to be important in small intestinal maturation and expression of genes related to intestinal differentiation and functions. Methods: We investigated target genes induced by co-treatment for 48 h with a glucocorticoid hormone agonist, dexamethasone (Dex), and a p44/42 MAPK inhibitor, P098059 (PD), in a small intestine-like cell line (Caco-2) using microarray analysis. We also investigated whether expression changes of the target genes induced by the co-treatment are associated with histone modifications around these genes. Results: Co-treatment of Caco-2 cells with Dex and PD enhanced several genes related to intestinal differentiation and functions such as SCNN1A, PXYD3, LCT and LOX. Induction of the SCNN1A gene was associated with increased presence of acetylated histone H3 and H4 and di-methylated histone H3 at lysine (K) 4 around the transcribed region of the gene, and induction of the PXYD3 gene was associated with increased presence of acetylated histones 1-13 and H4 from the promoter/enhancer to the transcribed region of the gene. Induction of LCT and LOX genes was associated with increased presence of acetylated histone H4 on the promoter/enhancer region of the genes. Conclusions: histone acetylation and/or histone H3 1(4 methylation around the promoter/enhancer or/and transcribed regions of target genes are associated with induction of the genes by co-treatment with Dex and PD in Caco-2 cells. General significance: The histone code is specific to each gene with respect to induction by glucocorticoid hormone and inhibition of p44/42 MAPK in Caco-2 cells. (C) 2013 Elsevier B.V. All rights reserved.

关键词： histone code Differentiation Caco-2 cells Glucocorticoid hormone p44/42 MAPK

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