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2.
Front Genet ; 14: 1257932, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38028583

RESUMO

Histone deacetylation is an important mechanism involved in human breast cancer tumorigenesis and recent veterinary oncology studies also demonstrate a similar relationship in some canine neoplasms. The use of HDAC inhibitors in vitro and in vivo has demonstrated antitumor action on several strains of human and animal cancers. The present study aims to correlate the expression of H3K9Ac, H4K12Ac, HDAC1, HDAC2 and HDAC6 in simple mammary carcinomas in dogs with clinicopathological parameters and overall survival time. To this end, 61 samples of simple breast carcinomas were analyzed by the immunohistochemistry technique with subsequent validation of the antibodies by the Western Blot technique. The expressions obtained via a semi-quantitative way were categorized by assigning scores and classified into high or low expressions according to the given score, except for HDAC6, when the marking percentage was considered and subdivided into high and low expressions using the median value. For statistical analysis, the chi-square test or Fisher exact test were used as univariate analysis and correspondence analysis as a multivariate test, in addition to the Kaplan-Meier survival analysis. In the studied samples, the highest frequencies were determined for the high expression proteins H4K12Ac (88.5%), HDAC2 (65.6%) and HDAC6 (56.7%) and the low expression proteins H3K9Ac (73.8%) and HDAC1 (54.1%). An association between the low expression of HDAC1 and the presence of lymph node metastasis (p = 0.035) was indicated by univariate analysis while the high expression of HDAC1 was associated with favorable prognostic factors, such as the absence of lymph node metastasis and low mitotic index by multivariate analysis. Also, by multivariate analysis, the low expression of HDAC6 was correlated with the low expression of Ki67, smaller tumors, and better prognosis factors as well. Protein expression was not correlated with patients' overall survival time (p > 0.05). The high expressions of HDAC2 and HDAC6 in mammary carcinomas in female dogs may be useful information for research involving therapeutic targets with iHDACs since their inhibition favors hyperacetylation and transcription of tumor suppressor genes.

3.
FASEB J ; 37(9): e23126, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37594040

RESUMO

The involvement of innate immune mediators to the Zika virus (ZIKV)-induced neuroinflammation is not yet well known. Here, we investigated whether neutrophil extracellular traps (NETs), which are scaffolds of DNA associated with proteins, have the potential to injure peripheral nervous. The tissue lesions were evaluated after adding NETs to dorsal root ganglia (DRG) explants and to DRG constituent cells or injecting them into mouse sciatic nerves. Identification of NET harmful components was achieved by pharmacological inhibition of NET constituents. We found that ZIKV inoculation into sciatic nerves recruited neutrophils and elicited the production of the cytokines CXCL1 and IL-1ß, classical NET inducers, but did not trigger NET formation. ZIKV blocked PMA- and CXCL8-induced NET release, but, in contrast, the ZIKV nonstructural protein (NS)-1 induced NET formation. NET-enriched supernatants were toxic to DRG explants, decreasing neurite area, length, and arborization. NETs were toxic to DRG constituent cells and affected myelinating cells. Myeloperoxidase (MPO) and histones were identified as the harmful component of NETs. NS1 injection into mouse sciatic nerves recruited neutrophils and triggered NET release and caspase-3 activation, events that were also elicited by the injection of purified MPO. In summary, we found that ZIKV NS1 protein induces NET formation, which causes nervous tissue damages. Our findings reveal new mechanisms leading to neuroinflammation by ZIKV.


Assuntos
Armadilhas Extracelulares , Infecção por Zika virus , Zika virus , Animais , Camundongos , Doenças Neuroinflamatórias , Nervo Isquiático
4.
Mol Neurobiol ; 60(9): 5013-5033, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37233974

RESUMO

Preclinical genetic studies have related stress early exposures with changes in gene regulatory mechanisms, including epigenetic alterations, such as modifications of DNA methylation, histone deacetylation, and histones acetylation. This study evaluates the effects of prenatal stress on the behavior, hypothalamus-pituitary-adrenal (HPA)-axis, and epigenetic parameters in stressed dams and their offspring. The rats were subjected to a protocol of chronic unpredictable mild stress on the fourteenth day of pregnancy until the birth of offspring. After birth, maternal care was evaluated for six days. Following weaning, the locomotor and depressive-like behaviors of the dams and their offspring (60 days old) were assessed. The HPA axis parameters were evaluated in serum from dams and offspring, and epigenetic parameters (histone acetyltransferase (HAT), histone deacetylase (HDAC), DNA methyltransferase (DNMT) activities, and the levels of histone H3 acetylated at lysine residue 9 (H3K9ac) and histone 3 acetylated at lysine residue 14 (H3K14ac)) were assessed in dams' and offspring' brains. Prenatal stress did not significantly influence maternal care; however, it induced manic behavior in female offspring. These behavioral alterations in the offspring were accompanied by hyperactivity of the HPA-axis, epigenetic adaptations in the activity of HDAC and DNMT, and acetylation in the histones H3K9 and H3K14. In addition, the prenatal stressed female offspring showed increased levels of ACTH compared to their male counterpart. Our findings reinforce the impact of prenatal stress on behavior, stress response, and epigenetic profile of offspring.


Assuntos
Sistema Hipotálamo-Hipofisário , Efeitos Tardios da Exposição Pré-Natal , Humanos , Gravidez , Ratos , Animais , Masculino , Feminino , Sistema Hipotálamo-Hipofisário/metabolismo , Histonas/metabolismo , Lisina , Efeitos Tardios da Exposição Pré-Natal/genética , Sistema Hipófise-Suprarrenal/metabolismo , Epigênese Genética , Estresse Psicológico/genética
5.
Medwave ; 23(3)2023 Apr 24.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-37094250

RESUMO

Rheumatoid arthritis is an autoimmune and inflammatory disease that predominantly affects the diarthrodial joints. In this pathology, environmental or behavioral factors can act in synergy with genetic predisposition, accelerating the onset and severity of the disease. This link between the environment and the genome is mediated by epigenetic marks on deoxyribonucleic acid, including its methylation, histone modification, and noncoding ribonucleic acid-mediated regulation. Epigenetics can generate heritable phenotypic changes, which are not determined by modifications in the deoxyribonucleic acid sequence and are therefore reversible. Therefore, diet, medications and other environmental factors would have the ability to modulate them. The identification of a specific epigenetic dysregulation can offer a better understanding of the pathophysiology of the disease and positively influence the prevention, diagnosis and development of new therapeutic targets.


La artritis reumatoide es una enfermedad autoinmune e inflamatoria que afecta de manera predominante a las articulaciones diartrodiales. En esta patología los factores ambientales o conductuales pueden actuar en sinergia con la predisposición genética, acelerando el inicio y la gravedad de la enfermedad. Este vínculo entre el medio ambiente y el genoma está mediado por marcas epigenéticas en el ácido desoxirribonucleico, incluyendo su metilación, la modificación de histonas y la regulación mediada por ácido ribonucleico no codificante. La epigenética puede generar cambios fenotípicos hereditarios, que no están determinados por modificaciones en la secuencia del ácido desoxirribonucleico y, en consecuencia, son reversibles. Por lo tanto la dieta, los medicamentos y otros factores ambientales, tendrían la capacidad de modularlos. La identificación de una desregulación epigenética específica, puede ofrecer una mayor comprensión de la fisiopatología de la enfermedad e influenciar positivamente en la prevención, diagnóstico y desarrollo de nuevas dianas terapéuticas.


Assuntos
Artrite Reumatoide , Metilação de DNA , Humanos , Histonas/genética , Histonas/metabolismo , Epigênese Genética , DNA
6.
Medwave ; 23(3): e2619, 28-04-2023. ilus
Artigo em Inglês, Espanhol | LILACS | ID: biblio-1436100

RESUMO

La artritis reumatoide es una enfermedad autoinmune e inflamatoria que afecta de manera predominante a las articulaciones diartrodiales. En esta patología los factores ambientales o conductuales pueden actuar en sinergia con la predisposición genética, acelerando el inicio y la gravedad de la enfermedad. Este vínculo entre el medio ambiente y el genoma está mediado por marcas epigenéticas en el ácido desoxirribonucleico, incluyendo su metilación, la modificación de histonas y la regulación mediada por ácido ribonucleico no codificante. La epigenética puede generar cambios fenotípicos hereditarios, que no están determinados por modificaciones en la secuencia del ácido desoxirribonucleico y, en consecuencia, son reversibles. Por lo tanto la dieta, los medicamentos y otros factores ambientales, tendrían la capacidad de modularlos. La identificación de una desregulación epigenética específica, puede ofrecer una mayor comprensión de la fisiopatología de la enfermedad e influenciar positivamente en la prevención, diagnóstico y desarrollo de nuevas dianas terapéuticas.


Rheumatoid arthritis is an autoimmune and inflammatory disease that predominantly affects the diarthrodial joints. In this pathology, environmental or behavioral factors can act in synergy with genetic predisposition, accelerating the onset and severity of the disease. This link between the environment and the genome is mediated by epigenetic marks on deoxyribonucleic acid, including its methylation, histone modification, and noncoding ribonucleic acid-mediated regulation. Epigenetics can generate heritable phenotypic changes, which are not determined by modifications in the deoxyribonucleic acid sequence and are therefore reversible. Therefore, diet, medications and other environmental factors would have the ability to modulate them. The identification of a specific epigenetic dysregulation can offer a better understanding of the pathophysiology of the disease and positively influence the prevention, diagnosis and development of new therapeutic targets.


Assuntos
Humanos , Artrite Reumatoide , Metilação de DNA , DNA , Histonas/genética , Histonas/metabolismo , Epigênese Genética
7.
Biomedicines ; 10(10)2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36289829

RESUMO

There is a consensus that epigenetic alterations play a key role in cancer initiation and its biology. Studies evaluating the modification in the DNA methylation and chromatin remodeling patterns, as well as gene regulation profile by non-coding RNAs (ncRNAs) have led to the development of novel therapeutic approaches to treat several tumor types. Indeed, despite clinical and translational challenges, combinatorial therapies employing agents targeting epigenetic modifications with conventional approaches have shown encouraging results. However, for rare neoplasia such as uterine leiomyosarcomas (LMS) and endometrial stromal sarcomas (ESS), treatment options are still limited. LMS has high chromosomal instability and molecular derangements, while ESS can present a specific gene fusion signature. Although they are the most frequent types of "pure" uterine sarcomas, these tumors are difficult to diagnose, have high rates of recurrence, and frequently develop resistance to current treatment options. The challenges involving the management of these tumors arise from the fact that the molecular mechanisms governing their progression have not been entirely elucidated. Hence, to fill this gap and highlight the importance of ongoing and future studies, we have cross-referenced the literature on uterine LMS and ESS and compiled the most relevant epigenetic studies, published between 2009 and 2022.

8.
Int J Mol Sci ; 23(15)2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35955838

RESUMO

During mitosis, many cellular structures are organized to segregate the replicated genome to the daughter cells. Chromatin is condensed to shape a mitotic chromosome. A multiprotein complex known as kinetochore is organized on a specific region of each chromosome, the centromere, which is defined by the presence of a histone H3 variant called CENP-A. The cytoskeleton is re-arranged to give rise to the mitotic spindle that binds to kinetochores and leads to the movement of chromosomes. How chromatin regulates different activities during mitosis is not well known. The role of histone post-translational modifications (HPTMs) in mitosis has been recently revealed. Specific HPTMs participate in local compaction during chromosome condensation. On the other hand, HPTMs are involved in CENP-A incorporation in the centromere region, an essential activity to maintain centromere identity. HPTMs also participate in the formation of regulatory protein complexes, such as the chromosomal passenger complex (CPC) and the spindle assembly checkpoint (SAC). Finally, we discuss how HPTMs can be modified by environmental factors and the possible consequences on chromosome segregation and genome stability.


Assuntos
Proteínas Cromossômicas não Histona , Histonas , Centrômero/genética , Centrômero/metabolismo , Proteína Centromérica A/metabolismo , Cromatina/genética , Proteínas Cromossômicas não Histona/metabolismo , Segregação de Cromossomos , Histonas/metabolismo , Cinetocoros/metabolismo , Mitose/genética , Processamento de Proteína Pós-Traducional
9.
Adv Exp Med Biol ; 1382: 95-107, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36029406

RESUMO

Post-translational modifications (PTMs) have a strong impact on many proteins across all kingdoms of life, affecting multiple functional and chemical properties of their protein recipients. With increasing knowledge about their functions, targets, and biological effects, dysregulations in PTMs have been implicated in various dysfunctions and diseases. One such target are histones, which compose the majority of the protein component of chromatin and the modulation of the 30+ PTMs that are known to affect them can have profound effects on chromatin state, gene expression, and DNA repair. In this review, the histone targets of PTMs are compiled in the context of neurological disorders, highlighting their specific biological roles and any previously implicated dysregulations in several classes of brain disease. Better understanding the pathogenic dysregulations of PTMs in such disorders can help to better understand their causes, as well as open doors to new possibilities for biomarkers and therapeutic targets.


Assuntos
Encefalopatias , Código das Histonas , Cromatina , Histonas , Humanos , Processamento de Proteína Pós-Traducional
10.
Comput Biol Med ; 148: 105895, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35926268

RESUMO

OBJECTIVE: To explore the molecular processes associated with cellular regulatory programs in patients with COVID-19, including gene activation or repression mediated by epigenetic mechanisms. We hypothesized that a comprehensive gene expression profiling of nasopharyngeal epithelial cells might expand our understanding of the pathogenic mechanisms of severe COVID-19. METHODS: We used single-cell RNA sequencing (scRNAseq) profiling of ciliated cells (n = 12,725) from healthy controls (SARS-CoV-2 negative n = 13) and patients with mild/moderate (n = 13) and severe (n = 14) COVID-19. ScRNAseq data at the patient level were used to perform gene set and pathway enrichment analyses. We prioritized candidate miRNA-target interactions and epigenetic mechanisms. RESULTS: We found that mild/moderate COVID-19 compared to healthy controls had upregulation of gene expression signatures associated with mitochondrial function, misfolded proteins, and membrane permeability. In addition, we found that compared to mild/moderate disease, severe COVID-19 had downregulation of epigenetic mechanisms, including DNA and histone H3K4 methylation and chromatin remodelling regulation. Furthermore, we found 11-ranked miRNAs that may explain miRNA-dependent regulation of histone methylation, some of which share seed sequences with SARS-CoV-2 miRNAs. CONCLUSION: Our results may provide novel insights into the epigenetic mechanisms mediating the clinical course of SARS-CoV-2 infection.


Assuntos
Fenômenos Biológicos , COVID-19 , MicroRNAs , Epigênese Genética , Perfilação da Expressão Gênica , Histonas , Humanos , SARS-CoV-2
11.
Front Cell Infect Microbiol ; 12: 901994, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35770070

RESUMO

Cystic echinococcosis (CE) is a zoonotic disease worldwide distributed, caused by the cestode Echinococcus granulosus sensu lato (E. granulosus), with an incidence rate of 50/100,000 person/year and a high prevalence in humans of 5-10%. Serology has variable sensitivity and specificity and low predictive values. Antigens used are from the hydatid fluid and recombinant antigens have not demonstrated superiority over hydatid fluid. A cell line called EGPE was obtained from E. granulosus sensu lato G1 strain from bovine liver. Serum from CE patients recognizes protein extracts from EGPE cells with higher sensitivity than protein extracts from hydatid fluid. In the present study, EGPE cell protein extracts and supernatants from cell colonies were eluted from a protein G affinity column performed with sera from 11 CE patients. LC-MS/MS proteomic analysis of the eluted proteins identified four E. granulosus histones: one histone H4 in the cell extract and supernatant, one histone H2A only in the cell extract, and two histones H2A only in the supernatant. This differential distribution of histones could reflect different parasite viability stages regarding their role in gene transcription and silencing and could interact with host cells. Bioinformatics tools characterized the linear and conformational epitopes involved in antibody recognition. The three-dimensional structure of each histone was obtained by molecular modeling and validated by molecular dynamics simulation and PCR confirmed the presence of the epitopes in the parasite genome. The three histones H2A were very different and had a less conserved sequence than the histone H4. Comparison of the histones of E. granulosus with those of other organisms showed exclusive regions for E. granulosus. Since histones play a role in the host-parasite relationship they could be good candidates to improve the predictive value of serology in CE.


Assuntos
Cistos , Equinococose , Echinococcus granulosus , Animais , Bovinos , Extratos Celulares , Cromatografia Líquida , Equinococose/epidemiologia , Equinococose/parasitologia , Echinococcus granulosus/genética , Epitopos de Linfócito B , Genótipo , Histonas , Humanos , Fígado , Hepatopatias , Proteômica , Espectrometria de Massas em Tandem
12.
J Comp Pathol ; 193: 51-58, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35487622

RESUMO

The objective of this study was to investigate the immunolabelling of acetylated histones and histone desacetylase (HDAC) enzymes in canine soft tissue sarcomas (STSs) and to correlate them with histological and clinical features in order to identify possible prognostic and therapeutic targets in these neoplasms. Fifteen canine STS samples were evaluated and were submitted to immunohistochemistry for acetylated histones 3 (H3) and 4 (H4) and deacetylating enzymes (HDAC1, HDAC2 and HDAC6). Intense immunolabelling of H4 was seen in comparison with H3. A strong positive correlation was observed between the H3 intensity score and the number of mitotic figures (P = 0.004, r = 0.7). Intense immunolabelling of HDAC1 was found in comparison to the expression of HDAC2 and HDAC6 in the evaluated STSs. This finding suggests that HDAC1 may be a potential target for HDAC inhibitors in STSs in dogs.


Assuntos
Doenças do Cão , Sarcoma , Animais , Cães , Histona Desacetilases/metabolismo , Histonas/metabolismo , Imuno-Histoquímica , Prognóstico , Sarcoma/veterinária
13.
J Proteomics ; 255: 104488, 2022 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-35065287

RESUMO

Lysine crotonylation (Kcr) is a newly discovered post-translational modification, which is structurally and functionally different from the widely studied lysine acetylation. Kcr is found on histones and non-histone proteins, participating in many biological processes through the regulation of chromatin remodeling, metabolism, cell cycle and cellular organization. Among plants, Kcr in histones is not found in the same lysine residues but increases gene expression when it is co-localized with lysine acetylation. Kcr in non-histone proteins is mainly found in the chloroplast, which provides new insight into photosynthesis. In this review, we discuss recent findings on plant Kcr in histone and non-histone proteins, highlighting its biological implications. These findings not only point to new functions for Kcr, but also reveal the mechanisms by which crotonylation regulates cellular processes in plants and may even change the general direction of epigenome and plant regulation.


Assuntos
Epigênese Genética , Lisina , Acetilação , Histonas/metabolismo , Lisina/metabolismo , Processamento de Proteína Pós-Traducional
14.
Front Genet ; 12: 654256, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34306008

RESUMO

The structure of eukaryotic genes is generally a combination of exons interrupted by intragenic non-coding DNA regions (introns) removed by RNA splicing to generate the mature mRNA. A fraction of genes, however, comprise a single coding exon with introns in their untranslated regions or are intronless genes (IGs), lacking introns entirely. The latter code for essential proteins involved in development, growth, and cell proliferation and their expression has been proposed to be highly specialized for neuro-specific functions and linked to cancer, neuropathies, and developmental disorders. The abundant presence of introns in eukaryotic genomes is pivotal for the precise control of gene expression. Notwithstanding, IGs exempting splicing events entail a higher transcriptional fidelity, making them even more valuable for regulatory roles. This work aimed to infer the functional role and evolutionary history of IGs centered on the mouse genome. IGs consist of a subgroup of genes with one exon including coding genes, non-coding genes, and pseudogenes, which conform approximately 6% of a total of 21,527 genes. To understand their prevalence, biological relevance, and evolution, we identified and studied 1,116 IG functional proteins validating their differential expression in transcriptomic data of embryonic mouse telencephalon. Our results showed that overall expression levels of IGs are lower than those of MEGs. However, strongly up-regulated IGs include transcription factors (TFs) such as the class 3 of POU (HMG Box), Neurog1, Olig1, and BHLHe22, BHLHe23, among other essential genes including the ß-cluster of protocadherins. Most striking was the finding that IG-encoded BHLH TFs fit the criteria to be classified as microproteins. Finally, predicted protein orthologs in other six genomes confirmed high conservation of IGs associated with regulating neural processes and with chromatin organization and epigenetic regulation in Vertebrata. Moreover, this study highlights that IGs are essential modulators of regulatory processes, such as the Wnt signaling pathway and biological processes as pivotal as sensory organ developing at a transcriptional and post-translational level. Overall, our results suggest that IG proteins have specialized, prevalent, and unique biological roles and that functional divergence between IGs and MEGs is likely to be the result of specific evolutionary constraints.

15.
Front Cell Dev Biol ; 9: 645518, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33959607

RESUMO

Valproic acid/sodium valproate (VPA), a drug originally prescribed as an anticonvulsant, has been widely reported to act on epigenetic marks by inducing histone acetylation, affecting the DNA and histone methylation status, and altering the expression of transcription factors, thus leading to modulation of gene expression. All these epigenetic changes have been associated with chromatin remodeling effects. The present minireview briefly reports the main effects of VPA on chromatin and image analysis and Fourier transform infrared (FTIR) microspectroscopy in association with molecular biology methodological approaches to investigate the VPA-induced changes in chromatin structure and at the higher-order supraorganizational level.

16.
Radiother Oncol ; 159: 48-59, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33741468

RESUMO

Radiotherapy, in addition to surgery and systemic chemotherapy, remains the core of the current clinical management of cancer. Radioresistance is one of the major causes of disease progression and mortality in cancer; therefore, it is a significant challenge in the treatment of locally advanced, recurrent and metastatic cancer. Epigenetic mechanisms that control hallmarks of cancer have a key role in the development of radiation resistance of cancer cells. Recent advances in DNA methylation, histone modification, chromatin remodeling and non-coding RNAs identified in the control of signal transduction pathways in cancer and cancer stem cells have provided even greater promise in the improvement of understanding cancer radioresistance. Many epigenetic drugs that target epigenetic enzymes revert the radioresistant phenotypes decreasing the possibility that resistant cancer cells will develop refractory tumors to radiotherapy. Epigenetic profiles identified as regulators of DNA damage repair, hypoxia, cell survival, apoptosis and invasion are determinants in the development of tumor radioresistance; hence, they also are promising in personalized medicine to develop novel targeted therapies or biomarkers to follow-up the effectiveness of radiotherapy. Now, it is clear that radiotherapy can influence a complex epigenetic network for transcriptional reprogramming, enabling the cells to adapt and avoid the effect of radiotherapy. This review aims to highlight the epigenetic modifications identified in cancer radioresistance and to discuss approaches to disable epigenetic networks to increase the sensitivity and specificity of radiotherapy.


Assuntos
Neoplasias , Apoptose , Metilação de DNA , Epigênese Genética , Humanos , Neoplasias/genética , Neoplasias/radioterapia , Transdução de Sinais
17.
Adv Exp Med Biol ; 1346: 131-154, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35113400

RESUMO

Eukaryotic DNA exist in the nuclei in the form of a complex with proteins called chromatin. Access to the information encoded in the DNA requires the opening of the chromatin. Modulation of the chromatin structure is therefore an important layer of regulation for DNA-templated processes. The basic unit of the chromatin is the nucleosome, which contains DNA wrapped around an octamer of histones, H2A, H2B, H3, and H4. Because histones are a structural part of the nucleosome, its modification can lead to changes in chromatin structure. Amino acid residues in histones could be modified with at least 20 different types of functional groups leading to a vast number of modified residues. Here, an overview of the histone modifications found in plants is provided. We focus mainly in proteomic-based studies either aimed to identify PTMs on purified histones or proteome-wide analysis of particular modifications. The strategies used for cataloging modifications in plants are also described. Profiling of histone modifications is important to begin to understand their functions as mediators of gene regulation in plant biological systems.


Assuntos
Histonas , Plantas/genética , Processamento de Proteína Pós-Traducional , Proteômica , Cromatina , Histonas/genética , Histonas/metabolismo , Nucleossomos/genética
18.
J Proteomics ; 231: 104020, 2021 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-33096306

RESUMO

Trypanosoma cruzi trypomastigotes adhere to extracellular matrix (ECM) to invade mammalian host cells regulating intracellular signaling pathways. Herein, resin-assisted enrichment of thiols combined with mass spectrometry were employed to map site-specific S-nitrosylated (SNO) proteins from T. cruzi trypomastigotes incubated (MTy) or not (Ty) with ECM. We confirmed the reduction of S-nitrosylation upon incubation with ECM, associated with a rewiring of the subcellular distribution and intracellular signaling pathways. Forty, 248 and 85 SNO-peptides were identified only in MTy, Ty or in both conditions, respectively. SNO proteins were enriched in ribosome, transport, carbohydrate and lipid metabolisms. Nitrosylation of histones H2B and H3 on Cys64 and Cys126, respectively, is described. Protein-protein interaction networks revealed ribosomal proteins, proteins involved in carbon and fatty acid metabolism to be among the enriched protein complexes. Kinases, phosphatases and enzymes involved in the metabolism of carbohydrates, lipids and amino acids were identified as nitrosylated and phosphorylated, suggesting a post-translational modifications crosstalk. In silico mapping of nitric oxide synthase (NOS) genes, previously uncharacterized, matched to four putative T. cruzi proteins expressing C-terminal NOS domain. Our results provide the first site-specific characterization of S-nitrosylated proteins in T. cruzi and their modulation upon ECM incubation before infection of the mammalian hosts. SIGNIFICANCE: Protein S-nitrosylation represents a major molecular mechanism for signal transduction by nitric oxide. We present for the first time a proteomic profile of S-nitrosylated proteins from infective forms of T. cruzi, showing a decrease in SNO proteins after incubation of the parasite with the extracellular matrix, a necessary step for the parasite invasion of the host mammalian cells. We also show for the first time nitrosylation of H2B (Cys64) and H3 (Cys126) histones, sites not conserved in higher eukaryotic cells, and suggest that some specific histone isoforms are sensitive to NO signaling. S-nitrosylation in H2B and H3 histones are more abundant in MTy. Moreover, proteins involved in translation, glycolytic pathway and fatty acid metabolism are enriched in the present dataset. Comparison of the SNO proteome and the phosphoproteome, obtained previously under the same experimental conditions, show that most of the proteins sharing both modifications are involved in metabolic pathways, transport and ribosome function. The data suggest that both PTMs are involved in reprogramming the metabolism of T. cruzi in response to environmental changes. Although NO synthesis was detected in T. cruzi, the identification of NOS remains elusive. Analysis in silico showed two genes similar in domains to NADPH-dependent cytochrome-P450 reductase and two putative oxidoreductases, but no oxygenase domain of NOS was mapped in the T. cruzi genome. It is tempting to speculate that NO synthase-like from T. cruzi and its early NO-mediated pathways triggered in response to host interaction constitute potential diagnostic and therapeutic targets.


Assuntos
Doença de Chagas , Trypanosoma cruzi , Animais , Matriz Extracelular , Proteoma , Proteômica
19.
Cent Nerv Syst Agents Med Chem ; 21(2): 142-147, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32972354

RESUMO

BACKGROUND: Cannabidiol (CBD), a non-psychotropic constituent of Cannabis sativa, has shown therapeutic promises by modulating several pathological conditions, including pain, epilepsy autism, among others. However, the molecular mechanism of action of CBD remains unknown and recent data suggest the engagement on CBD´s effects of nuclear elements, such as histone activity. AIM: This study assessed the changes in the post-translational modification (PTM) on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 in several brain regions of rats after the administration of CBD (20 mg/Kg/i.p.). OBJECTIVE: To evaluate the effects on the PTM of histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 levels in the cerebral cortex, hypothalamus and pons of CBD-treated rats. METHODS: Ten adult rats were randomly assigned into 2 groups: Control or CBD (20 mg/Kg/i.p). Animals were sacrificed after treatments and brains were collected for dissections of the cerebral cortex, hypothalamus and pons. Samples were analyzed for PTM on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 levels by Western blot procedure. RESULTS: CBD increased the PTM levels on the histones H3K4Me3, H3K9ac, and H3K27Me3 in the cerebral cortex whereas no significant differences were found in H3K9Me2 and H3K36Me2. In addition, in the hypothalamus, CBD decreased the contents of H3K9ac while no significant effects were observed in H3K4Me3, H3K9Me2, H3K27Me3, and H3K36Me2. Lastly, in the pons, CBD- treated rats showed a significant decline on the PTM levels of H3K4Me3 whereas no statistical differences were found in H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2. CONCLUSION: The study showed that CBD induced differential effects in levels of PTM on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 in several brain regions.


Assuntos
Canabidiol , Histonas , Animais , Canabidiol/farmacologia , Córtex Cerebral/metabolismo , Histonas/genética , Histonas/metabolismo , Hipotálamo/metabolismo , Ponte/metabolismo , Processamento de Proteína Pós-Traducional , Ratos
20.
Front Genet ; 11: 780, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32765595

RESUMO

The genome of eukaryotes is highly organized within the cell nucleus, this organization per se elicits gene regulation and favors other mechanisms like cell memory throughout histones and their post-translational modifications. In highly specialized cells, like sperm, the genome is mostly organized by protamines, yet a significant portion of it remains organized by histones. This protamine-histone-DNA organization, known as sperm epigenome, is established during spermiogenesis. Specific histones and their post-translational modifications are retained at specific genomic sites and during embryo development these sites recapitulate their histone profile that harbored in the sperm nucleus. It is known that histones are the conduit of epigenetic memory from cell to cell, hence histones in the sperm epigenome may have a role in transmitting epigenetic memory from the sperm to the embryo. However, the exact function and mechanism of histone retention remains elusive. During spermatogenesis, most of the histones that organize the genome are replaced by protamines and their retention at specific regions may be deeply intertwined with the eviction and replacement mechanism. In this review we will cover some relevant aspects of histone replacement that in turn may help us to contextualize histone retention. In the end, we focus on the architectonical protein CTCF that is, so far, the only factor that has been directly linked to the histone retention process.

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