- MeSH
- Histone Code * MeSH
- Humans MeSH
- Neoplasms metabolism MeSH
- DNA Damage * MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
Arbitrariness in the genetic code is one of the main reasons for a linguistic approach to molecular biology: the genetic code is usually understood as an arbitrary relation between amino acids and nucleobases. However, from a semiotic point of view, arbitrariness should not be the only condition for definition of a code, consequently it is not completely correct to talk about "code" in this case. Yet we suppose that there exist a code in the process of protein synthesis, but on a higher level than the nucleic bases chains. Semiotically, a code should be always associated with a function and we propose to define the genetic code not only relationally (in basis of relation between nucleobases and amino acids) but also in terms of function (function of a protein as meaning of the code). Even if the functional definition of meaning in the genetic code has been discussed in the field of biosemiotics, its further implications have not been considered. In fact, if the function of a protein represents the meaning of the genetic code (the sign's object), then it is crucial to reconsider the notion of its expression (the sign) as well. In our contribution, we will show that the actual model of the genetic code is not the only possible and we will propose a more appropriate model from a semiotic point of view.
MAIN CONCLUSION: Contrasting patterns of histone modifications between the X and Y chromosome in Silene latifolia show euchromatic histone mark depletion on the Y chromosome and indicate hyperactivation of one X chromosome in females. Silene latifolia (white campion) is a dioecious plant with heteromorphic sex chromosomes (24, XX in females and 24, XY in males), and a genetically degenerated Y chromosome that is 1.4 times larger than the X chromosome. Although the two sex chromosomes differ in their DNA content, information about epigenetic histone marks and evidence of their function are scarce. We performed immunolabeling experiments using antibodies specific for active and suppressive histone modifications as well as pericentromere-specific histone modifications. We show that the Y chromosome is partially depleted of histone modifications important for transcriptionally active chromatin, and carries these marks only in the pseudo-autosomal region, but that it is not enriched for suppressive and pericentromere histone marks. We also show that two of the active marks are specifically enriched in one of the X chromosomes in females and in the X chromosome in males. Our data support recent findings that genetic imprinting mediates dosage compensation of sex chromosomes in S. latifolia.
- MeSH
- Chromosomes, Plant genetics MeSH
- Epigenesis, Genetic * MeSH
- Histone Code genetics MeSH
- Silene genetics MeSH
- Publication type
- Journal Article MeSH
Understanding the epigenetics of tumor cells is of clinical significance for the treatment of cancer, and thus, chemists have focused their efforts on the synthesis of new generation of inhibitors of histone deacetylases (HDACs) or methylation-specific enzymes as novel important anti-cancer drugs. Here, we tested whether the histone signature and DNA methylation in multiple myeloma (MM) and leukemia cells is tumor-specific as compared with that in non-malignant lymphoblastoid cells. We observed a distinct histone signature in c-myc, Mcl-1, and ribosomal gene loci in MOLP8 MM and K562 leukemia cells, when compared with lymphoblastoid cells. Histone and DNA methylation patterns in MOLP8 cells were partially modified by the clinically promising HDAC inhibitor, vorinostat. In comparison with lymphoblastoid WIL2NS cells, MOLP8 cells and K562 cells were characterized by an absence of the gene silencing marker H3K9me2 in the c-myc and ribosomal genes. However, high levels of H3K27me3 were detected in the promoters and coding regions of selected genomic regions in these cells. Treatment by vorinostat increased the level of DNA methylation at the c-myc promoter, and this alteration was accompanied by a decrease in c-MYC protein. In MOLP8 cells, vorinostat significantly increased the H3K9 acetylation in the Mcl-1 coding regions and promoter. Both MOLP8 and K562 leukemia cells were characterized by decreased levels of H3K9me2 in the Mcl-1 gene as compared with lymphoblastoid WIL2NS cells. Lower levels of H3K9me1 in the Mcl-1 promoter, however, were specific for MM cells as compared with the other cell types studied. In other MM and leukemia cell lines, COLO677, OPM2, and U937, the ribosomal genes were less prone to epigenetic heterogeneity as compared to the c-myc and Mcl-1 proto-oncogenes. Taken together, these data describe both tumor-specific and loci-specific histone signature and DNA methylation profiles.
- MeSH
- Chromatin Immunoprecipitation MeSH
- Epigenesis, Genetic genetics MeSH
- Fluorescent Antibody Technique MeSH
- Histones genetics MeSH
- Leukemia genetics MeSH
- Humans MeSH
- DNA Methylation MeSH
- Multiple Myeloma genetics MeSH
- Cell Line, Tumor MeSH
- Promoter Regions, Genetic genetics MeSH
- Gene Expression Profiling MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
A high degree of developmental plasticity enables plants to adapt to continuous, often unfavorable and unpredictable changes in their environment. At the molecular level, adaptive advantages for plants are primarily provided by epigenetic machinery including DNA methylation, histone modifications, and the activity of noncoding RNA molecules. Using a mass spectrometry-based proteomic approach, we examined the levels of acetylated histone peptide forms in Arabidopsis plants with a loss of function of histone deacetylase 6 (HDA6), and in plants germinated in the presence of HDA inhibitors trichostatin A (TSA) and sodium butyrate (NaB). Our analyses revealed particular lysine sites at histone sequences targeted by the HDA6 enzyme, and by TSA- and NaB-sensitive HDAs. Compared with plants exposed to drugs, more dramatic changes in the overall profiles of histone post-translational modifications were identified in hda6 mutants. However, loss of HDA6 was not sufficient by itself to induce hyperacetylation to the maximum degree, implying complementary activities of other HDAs. In contrast to hda6 mutants that did not exhibit any obvious phenotypic defects, the phenotypes of seedlings exposed to HDA inhibitors were markedly affected, showing that the effect of these drugs on early plant development is not limited to the modulation of histone acetylation levels.
- MeSH
- Arabidopsis genetics growth & development MeSH
- Histone Deacetylases genetics MeSH
- Histone Code drug effects genetics MeSH
- Histone Deacetylase Inhibitors pharmacology MeSH
- Germination genetics MeSH
- Butyric Acid pharmacology MeSH
- Hydroxamic Acids pharmacology MeSH
- DNA Methylation drug effects MeSH
- Arabidopsis Proteins antagonists & inhibitors genetics MeSH
- Proteomics * MeSH
- Gene Expression Regulation, Plant MeSH
- Seedlings drug effects genetics MeSH
- Gene Silencing MeSH
- Plant Development drug effects genetics MeSH
- Publication type
- Journal Article MeSH
Epigenetic mechanisms have not been characterized in ticks despite their importance as vectors of human and animal diseases worldwide. The objective of this study was to characterize the histones and histone modifying enzymes (HMEs) of the tick vector Ixodes scapularis and their role during Anaplasma phagocytophilum infection. We first identified 5 histones and 34 HMEs in I. scapularis in comparison with similar proteins in model organisms. Then, we used transcriptomic and proteomic data to analyze the mRNA and protein levels of I. scapularis histones and HMEs in response to A. phagocytophilum infection of tick tissues and cultured cells. Finally, selected HMEs were functionally characterized by pharmacological studies in cultured tick cells. The results suggest that A. phagocytophilum manipulates tick cell epigenetics to increase I. scapularis p300/CBP, histone deacetylase, and Sirtuin levels, resulting in an inhibition of cell apoptosis that in turn facilitates pathogen infection and multiplication. These results also suggest that a compensatory mechanism might exist by which A. phagocytophilum manipulates tick HMEs to regulate transcription and apoptosis in a tissue-specific manner to facilitate infection, but preserving tick fitness to guarantee survival of both pathogens and ticks. Our study also indicates that the pathogen manipulates arthropod and vertebrate cell epigenetics in similar ways to inhibit the host response to infection. Epigenetic regulation of tick biological processes is an essential element of the infection by A. phagocytophilum and the study of the mechanisms and principal actors involved is likely to provide clues for the development of anti-tick drugs and vaccines.
- MeSH
- Anaplasma phagocytophilum genetics MeSH
- Apoptosis genetics MeSH
- Cell Line MeSH
- Epigenesis, Genetic * MeSH
- Histone Code genetics MeSH
- Histones genetics metabolism MeSH
- Insect Vectors genetics MeSH
- Host-Pathogen Interactions genetics MeSH
- Ixodes genetics MeSH
- Humans MeSH
- RNA, Messenger biosynthesis genetics MeSH
- p300-CBP Transcription Factors biosynthesis genetics MeSH
- Transcriptome genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Recent studies have shown that histone code dictates the type and structure of chromatin. Bearing in mind the importance of A-type lamins for chromatin arrangement, we studied the effect of trichostatin A (TSA)-induced histone hyperacetylation in lamin A/C-deficient (LMNA-/-) fibroblasts. Lamin A/C deficiency caused condensation of chromosome territories and the nuclear reorganization of centromeric heterochromatin, which was accompanied by the appearance of a chain-like morphology of HP1beta foci. Conversely, histone deacetylase (HDAC) inhibition induced de-condensation of chromosome territories, which compensated the effect of lamin A/C deficiency on chromosome regions. The amount of heterochromatin in the area associated with the nuclear membrane was significantly reduced in LMNA-/- cells when compared with lamin A/C-positive (LMNA+/+) fibroblasts. TSA also decreased the amount of peripheral heterochromatin, similarly as lamin A/C deficiency. In both LMNA+/+ and LMNA-/- cells, physically larger chromosomes were positioned more peripherally as compared with the smaller ones, even after TSA treatment. Our observations indicate that lamin A/C deficiency causes not only reorganization of chromatin and some chromatin-associated domains, but also has an impact on the extent of chromosome condensation. As HDAC inhibition can compensate the lamin A/C-dependent chromatin changes, the interaction between lamins and specifically modified histones may play an important role in higher-order chromatin organization, which influences transcriptional activity.
- MeSH
- Acetylation drug effects MeSH
- Cell Nucleus metabolism MeSH
- Centromere metabolism MeSH
- Chromatin metabolism drug effects MeSH
- Fibroblasts metabolism MeSH
- Financing, Organized MeSH
- Heterochromatin metabolism MeSH
- Enzyme Inhibitors pharmacology MeSH
- Histone Deacetylase Inhibitors MeSH
- Nuclear Proteins metabolism MeSH
- Hydroxamic Acids pharmacology MeSH
- Lamin Type A genetics metabolism deficiency MeSH
- Lamin Type B metabolism MeSH
- Mice MeSH
- Chromatin Assembly and Disassembly drug effects MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
Uveálny melanóm (UM) je závažné onkologické ochorenie, ktoré vedie ku vzniku metastatickej choroby u viac ako 50 % pacientov. Napriek zlepšeniu lokálnej liečby, stále neexistuje efektívna terapia, ktorá by zabránila rozvoju metastáz. Preto si toto ochorenie vyžaduje intenzívny výskum, zameraný na identifikáciu nových liečebných stratégií. V predklinických modeloch UM bolo dokázané, že epigenetické liečivá zvyšujú senzitivitu rezistentných nádorových buniek na liečbu. Úspešné použitie inhibítorov histón deacetyláz, ktoré u nádorových buniek indukovali zastavenie bunkového cyklu, reprogramovanie konzistentné s melanocytovou diferenciáciou a inhibíciu rastu nádorov v predklinických modeloch, dokazuje úlohu epigenetickej regulácie v metastázovaní UM. Hlbšie pochopenie úlohy epigenetických zmien v patogenéze UM by mohlo prispieť k objaveniu účinnejších liečiv, ktoré v kombinácii s tradičnými prístupmi môžu priniesť lepšie terapeutické výsledky pre pacientov s vysokým rizikom progresie ochorenia.
Uveal melanoma (UM) is a deadly cancer that leads to metastatic disease in more than 50 % of the patients. Despite the improvement in the treatment of primary disease, there is still no effective therapy to prevent the development of metastases. Therefore, the disease requires intensive research to identify new treatment strategies. In preclinical UM models, epigenetic drugs have been shown to increase the sensitivity of resistant tumour cells to treatment. The successful use of histone deacetylase inhibitors, which induced cell cycle arrest, reprogramming consistent with melanocyte differentiation and inhibition of tumour growth in preclinical models, demonstrates the role of epigenetic regulation in UM metastasis. Identification of epigenetic changes associated with UM development an progression could contribute to the discovery of more effective drugs that, in combination with traditional approaches, may yield better therapeutic results for high-risk patients.
- MeSH
- Epigenesis, Genetic MeSH
- Histone Code MeSH
- Humans MeSH
- DNA Methylation MeSH
- Uveal Neoplasms * genetics therapy MeSH
- RNA, Untranslated MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
