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1.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445674

RESUMO

Background: DNA methylation is an epigenetic control mechanism that may be altered by environmental exposures. We have previously reported that in utero exposure to the mycotoxin and liver carcinogen aflatoxin B1 from the maternal diet, as measured using biomarkers in the mothers' blood, was associated with differential DNA methylation in white blood cells of 6-month-old infants from The Gambia. Methods: Here we examined aflatoxin B1-associated differential DNA methylation in white blood cells of 24-month-old children from the same population (n = 244), in relation to the child's dietary exposure assessed using aflatoxin albumin biomarkers in blood samples collected at 6, 12 and 18 months of age. HM450 BeadChip arrays were used to assess DNA methylation, with data compared to aflatoxin albumin adduct levels using two approaches; a continuous model comparing aflatoxin adducts measured in samples collected at 18 months to DNA methylation at 24 months, and a categorical time-dose model that took into account aflatoxin adduct levels at 6, 12 and 18 months, for comparison to DNA methylation at 24 months. Results: Geometric mean (95% confidence intervals) for aflatoxin albumin levels were 3.78 (3.29, 4.34) at 6 months, 25.1 (21.67, 29.13) at 12 months and 49.48 (43.34, 56.49) at 18 months of age. A number of differentially methylated CpG positions and regions were associated with aflatoxin exposure, some of which affected gene expression. Pathway analysis highlighted effects on genes involved with with inflammatory, signalling and growth pathways. Conclusions: This study provides further evidence that exposure to aflatoxin in early childhood may impact on DNA methylation.


Assuntos
Aflatoxina B1/efeitos adversos , Metilação de DNA/efeitos dos fármacos , Exposição Ambiental/efeitos adversos , Experiências Adversas da Infância , Aflatoxinas/efeitos adversos , Aflatoxinas/análise , Aflatoxinas/sangue , Albuminas/análise , Pré-Escolar , DNA/metabolismo , Metilação de DNA/genética , Epigênese Genética/genética , Epigenômica/métodos , Feminino , Gâmbia/epidemiologia , Humanos , Lactente , Leucócitos/metabolismo , Masculino
2.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445123

RESUMO

Atherosclerosis represents one of the major causes of death globally. The high mortality rates and limitations of current therapeutic modalities have urged researchers to explore potential alternative therapies. The clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) system is commonly deployed for investigating the genetic aspects of Atherosclerosis. Besides, advances in CRISPR/Cas system has led to extensive options for researchers to study the pathogenesis of this disease. The recent discovery of Cas9 variants, such as dCas9, Cas9n, and xCas9 have been established for various applications, including single base editing, regulation of gene expression, live-cell imaging, epigenetic modification, and genome landscaping. Meanwhile, other Cas proteins, such as Cas12 and Cas13, are gaining popularity for their applications in nucleic acid detection and single-base DNA/RNA modifications. To date, many studies have utilized the CRISPR/Cas9 system to generate disease models of atherosclerosis and identify potential molecular targets that are associated with atherosclerosis. These studies provided proof-of-concept evidence which have established the feasibility of implementing the CRISPR/Cas system in correcting disease-causing alleles. The CRISPR/Cas system holds great potential to be developed as a targeted treatment for patients who are suffering from atherosclerosis. This review highlights the advances in CRISPR/Cas systems and their applications in establishing pathogenetic and therapeutic role of specific genes in atherosclerosis.


Assuntos
Aterosclerose/genética , Sistemas CRISPR-Cas/genética , Animais , DNA/genética , Epigênese Genética/genética , Edição de Genes/métodos , Expressão Gênica/genética , Genoma/genética , Humanos , RNA/genética , RNA Guia/genética
3.
Nat Commun ; 12(1): 4913, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389722

RESUMO

Epitranscriptomic mechanisms linking tRNA function and the brain proteome to cognition and complex behaviors are not well described. Here, we report bi-directional changes in depression-related behaviors after genetic disruption of neuronal tRNA cytosine methylation, including conditional ablation and transgene-derived overexpression of Nsun2 in the mouse prefrontal cortex (PFC). Neuronal Nsun2-deficiency was associated with a decrease in tRNA m5C levels, resulting in deficits in expression of 70% of tRNAGly isodecoders. Altogether, 1488/5820 proteins changed upon neuronal Nsun2-deficiency, in conjunction with glycine codon-specific defects in translational efficiencies. Loss of Gly-rich proteins critical for glutamatergic neurotransmission was associated with impaired synaptic signaling at PFC pyramidal neurons and defective contextual fear memory. Changes in the neuronal translatome were also associated with a 146% increase in glycine biosynthesis. These findings highlight the methylation sensitivity of glycinergic tRNAs in the adult PFC. Furthermore, they link synaptic plasticity and complex behaviors to epitranscriptomic modifications of cognate tRNAs and the proteomic homeostasis associated with specific amino acids.


Assuntos
Transtorno Depressivo/fisiopatologia , Epigênese Genética/genética , Metiltransferases/genética , Proteoma/metabolismo , RNA de Transferência/genética , Transmissão Sináptica/genética , Animais , Transtorno Depressivo/genética , Transtorno Depressivo/metabolismo , Perfilação da Expressão Gênica/métodos , Metiltransferases/deficiência , Metiltransferases/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neurônios/metabolismo , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiologia , Proteômica/métodos , RNA de Transferência/metabolismo , Transdução de Sinais/genética
4.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203193

RESUMO

Chromatin consists of a complex of DNA and histone proteins as its core components and plays an important role in both packaging DNA and regulating DNA metabolic pathways such as DNA replication, transcription, recombination, and chromosome segregation. Proper functioning of chromatin further involves a network of interactions among molecular complexes that modify chromatin structure and organization to affect the accessibility of DNA to transcription factors leading to the activation or repression of the transcription of target DNA loci. Based on its structure and compaction state, chromatin is categorized into euchromatin, heterochromatin, and centromeric chromatin. In this review, we discuss distinct chromatin factors and molecular complexes that constitute euchromatin-open chromatin structure associated with active transcription; heterochromatin-less accessible chromatin associated with silencing; centromeric chromatin-the site of spindle binding in chromosome segregation.


Assuntos
Centrômero/metabolismo , Eucromatina/metabolismo , Heterocromatina/metabolismo , Animais , Centrômero/genética , Cromatina/genética , Cromatina/metabolismo , Epigênese Genética/genética , Eucromatina/genética , Heterocromatina/genética , Humanos
5.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203243

RESUMO

The gut microbiota exists throughout the full life cycle of the human body, and it has been proven to have extensive impacts on health and disease. Accumulating evidence demonstrates that the interplay between gut microbiota and host epigenetics plays a multifaceted role in health maintenance and disease prevention. Intestinal microflora, along with their metabolites, could regulate multiple epigenetic pathways; e.g., DNA methylation, miRNA, or histone modification. Moreover, epigenetic factors can serve as mediators to coordinate gut microbiota within the host. Aiming to dissect this interplay mechanism, the present review summarizes the research profile of gut microbiota and epigenetics in detail, and further interprets the biofunctions of this interplay, especially the regulation of intestinal inflammation, the improvement of metabolic disturbances, and the inhibition of colitis events. This review provides new insights into the interplay of epigenetics and gut microbiota, and attempts to reveal the mysteries of health maintenance and disease prevention from this new perspective.


Assuntos
Epigênese Genética/genética , Animais , Metilação de DNA/genética , Metilação de DNA/fisiologia , Epigenômica , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/fisiologia , Humanos , MicroRNAs/metabolismo
6.
J Immunol ; 207(4): 1044-1054, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34330753

RESUMO

Eosinophils develop in the bone marrow from hematopoietic progenitors into mature cells capable of a plethora of immunomodulatory roles via the choreographed process of eosinophilopoiesis. However, the gene regulatory elements and transcription factors (TFs) orchestrating this process remain largely unknown. The potency and resulting diversity fundamental to an eosinophil's complex immunomodulatory functions and tissue specialization likely result from dynamic epigenetic regulation of the eosinophil genome, a dynamic eosinophil regulome. In this study, we applied a global approach using broad-range, next-generation sequencing to identify a repertoire of eosinophil-specific enhancers. We identified over 8200 active enhancers located within 1-20 kB of expressed eosinophil genes. TF binding motif analysis revealed PU.1 (Spi1) motif enrichment in eosinophil enhancers, and chromatin immunoprecipitation coupled with massively parallel sequencing confirmed PU.1 binding in likely enhancers of genes highly expressed in eosinophils. A substantial proportion (>25%) of these PU.1-bound enhancers were unique to murine, culture-derived eosinophils when compared among enhancers of highly expressed genes of three closely related myeloid cell subsets (macrophages, neutrophils, and immature granulocytes). Gene ontology analysis of eosinophil-specific, PU.1-bound enhancers revealed enrichment for genes involved in migration, proliferation, degranulation, and survival. Furthermore, eosinophil-specific superenhancers were enriched in genes whose homologs are associated with risk loci for eosinophilia and allergic diseases. Our collective data identify eosinophil-specific enhancers regulating key eosinophil genes through epigenetic mechanisms (H3K27 acetylation) and TF binding (PU.1).


Assuntos
Cromatina/genética , Eosinófilos/metabolismo , Epigênese Genética/genética , Ligação Proteica/genética , Proteínas Proto-Oncogênicas/genética , Transativadores/genética , Animais , Células Cultivadas , Camundongos , Camundongos Endogâmicos BALB C , Células Mieloides , Sequências Reguladoras de Ácido Nucleico/genética , Fatores de Transcrição/genética
7.
Nat Immunol ; 22(8): 1020-1029, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34312547

RESUMO

T cell exhaustion is an induced state of dysfunction that arises in response to chronic infection and cancer. Exhausted CD8+ T cells acquire a distinct epigenetic state, but it is not known whether that chromatin landscape is fixed or plastic following the resolution of a chronic infection. Here we show that the epigenetic state of exhaustion is largely irreversible, even after curative therapy. Analysis of chromatin accessibility in HCV- and HIV-specific responses identifies a core epigenetic program of exhaustion in CD8+ T cells, which undergoes only limited remodeling before and after resolution of infection. Moreover, canonical features of exhaustion, including super-enhancers near the genes TOX and HIF1A, remain 'epigenetically scarred.' T cell exhaustion is therefore a conserved epigenetic state that becomes fixed and persists independent of chronic antigen stimulation and inflammation. Therapeutic efforts to reverse T cell exhaustion may require new approaches that increase the epigenetic plasticity of exhausted T cells.


Assuntos
Antígenos Virais/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Hepacivirus/imunologia , Hepatite C Crônica/imunologia , Memória Imunológica/imunologia , 2-Naftilamina/uso terapêutico , Anilidas/uso terapêutico , Antivirais/uso terapêutico , Cromatina/metabolismo , Ciclopropanos/uso terapêutico , Epigênese Genética/genética , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Proteínas de Grupo de Alta Mobilidade/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Lactamas Macrocíclicas/uso terapêutico , Prolina/análogos & derivados , Prolina/uso terapêutico , Ribavirina/uso terapêutico , Ritonavir/uso terapêutico , Sulfonamidas/uso terapêutico , Uracila/análogos & derivados , Uracila/uso terapêutico , Valina/uso terapêutico
8.
Molecules ; 26(14)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34299537

RESUMO

Microbial natural products are an invaluable resource for the biotechnological industry. Genome mining studies have highlighted the huge biosynthetic potential of fungi, which is underexploited by standard fermentation conditions. Epigenetic effectors and/or cultivation-based approaches have successfully been applied to activate cryptic biosynthetic pathways in order to produce the chemical diversity suggested in available fungal genomes. The addition of Suberoylanilide Hydroxamic Acid to fermentation processes was evaluated to assess its effect on the metabolomic diversity of a taxonomically diverse fungal population. Here, metabolomic methodologies were implemented to identify changes in secondary metabolite profiles to determine the best fermentation conditions. The results confirmed previously described effects of the epigenetic modifier on the metabolism of a population of 232 wide diverse South Africa fungal strains cultured in different fermentation media where the induction of differential metabolites was observed. Furthermore, one solid-state fermentation (BRFT medium), two classic successful liquid fermentation media (LSFM and YES) and two new liquid media formulations (MCKX and SMK-II) were compared to identify the most productive conditions for the different populations of taxonomic subgroups.


Assuntos
Epigênese Genética/genética , Fungos/genética , Folhas de Planta/microbiologia , Produtos Biológicos/metabolismo , Vias Biossintéticas/genética , Biotecnologia/métodos , Meios de Cultura/metabolismo , Fermentação/genética , Genoma Fúngico/genética , Metabolômica/métodos , África do Sul
9.
Biomolecules ; 11(7)2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209228

RESUMO

Rett syndrome (RTT) is an extremely invalidating, cureless, developmental disorder, and it is considered one of the leading causes of intellectual disability in female individuals. The vast majority of RTT cases are caused by de novo mutations in the X-linked Methyl-CpG binding protein 2 (MECP2) gene, which encodes a multifunctional reader of methylated DNA. MeCP2 is a master epigenetic modulator of gene expression, with a role in the organization of global chromatin architecture. Based on its interaction with multiple molecular partners and the diverse epigenetic scenario, MeCP2 triggers several downstream mechanisms, also influencing the epigenetic context, and thus leading to transcriptional activation or repression. In this frame, it is conceivable that defects in such a multifaceted factor as MeCP2 lead to large-scale alterations of the epigenome, ranging from an unbalanced deposition of epigenetic modifications to a transcriptional alteration of both protein-coding and non-coding genes, with critical consequences on multiple downstream biological processes. In this review, we provide an overview of the current knowledge concerning the transcriptomic and epigenomic alterations found in RTT patients and animal models.


Assuntos
Epigênese Genética/genética , Síndrome de Rett/genética , Transcriptoma/genética , Cromatina , Metilação de DNA , Epigenômica/métodos , Expressão Gênica/genética , Histonas/genética , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , RNA não Traduzido/genética , Síndrome de Rett/metabolismo , Síndrome de Rett/fisiopatologia , Ativação Transcricional
10.
Nat Immunol ; 22(8): 1008-1019, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34312545

RESUMO

Exhausted CD8 T cells (TEX) are a distinct state of T cell differentiation associated with failure to clear chronic viruses and cancer. Immunotherapies such as PD-1 blockade can reinvigorate TEX cells, but reinvigoration is not durable. A major unanswered question is whether TEX cells differentiate into functional durable memory T cells (TMEM) upon antigen clearance. Here, using a mouse model, we found that upon eliminating chronic antigenic stimulation, TEX cells partially (re)acquire phenotypic and transcriptional features of TMEM cells. These 'recovering' TEX cells originated from the T cell factor (TCF-1+) TEX progenitor subset. Nevertheless, the recall capacity of these recovering TEX cells remained compromised as compared to TMEM cells. Chromatin-accessibility profiling revealed a failure to recover core memory epigenetic circuits and maintenance of a largely exhausted open chromatin landscape. Thus, despite some phenotypic and transcriptional recovery upon antigen clearance, exhaustion leaves durable epigenetic scars constraining future immune responses. These results support epigenetic remodeling interventions for TEX cell-targeted immunotherapies.


Assuntos
Antígenos Virais/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Memória Imunológica/imunologia , Coriomeningite Linfocítica/imunologia , Animais , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular/imunologia , Linhagem Celular , Chlorocebus aethiops , Cricetinae , Epigênese Genética/genética , Feminino , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transcrição Genética/genética , Células Vero
11.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299232

RESUMO

The genetic architecture of complex traits is multifactorial. Genome-wide association studies (GWASs) have identified risk loci for complex traits and diseases that are disproportionately located at the non-coding regions of the genome. On the other hand, we have just begun to understand the regulatory roles of the non-coding genome, making it challenging to precisely interpret the functions of non-coding variants associated with complex diseases. Additionally, the epigenome plays an active role in mediating cellular responses to fluctuations of sensory or environmental stimuli. However, it remains unclear how exactly non-coding elements associate with epigenetic modifications to regulate gene expression changes and mediate phenotypic outcomes. Therefore, finer interrogations of the human epigenomic landscape in associating with non-coding variants are warranted. Recently, chromatin-profiling techniques have vastly improved our understanding of the numerous functions mediated by the epigenome and DNA structure. Here, we review various chromatin-profiling techniques, such as assays of chromatin accessibility, nucleosome distribution, histone modifications, and chromatin topology, and discuss their applications in unraveling the brain epigenome and etiology of complex traits at tissue homogenate and single-cell resolution. These techniques have elucidated compositional and structural organizing principles of the chromatin environment. Taken together, we believe that high-resolution epigenomic and DNA structure profiling will be one of the best ways to elucidate how non-coding genetic variations impact complex diseases, ultimately allowing us to pinpoint cell-type targets with therapeutic potential.


Assuntos
Cromatina/genética , Cromatina/metabolismo , Cromatina/fisiologia , Sítios de Ligação/genética , Imunoprecipitação da Cromatina/métodos , Epigênese Genética/genética , Epigenoma/genética , Epigenômica/métodos , Regulação da Expressão Gênica/genética , Genoma , Estudo de Associação Genômica Ampla/métodos , Código das Histonas/genética , Humanos , Herança Multifatorial/genética , Nucleossomos/metabolismo , Nucleossomos/fisiologia , Polimorfismo de Nucleotídeo Único/genética , RNA não Traduzido/genética , RNA não Traduzido/metabolismo
12.
Molecules ; 26(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200173

RESUMO

Neuropeptides serve as neurohormones and local paracrine regulators that control neural networks regulating behavior, endocrine system and sensorimotor functions. Their expression is characterized by exceptionally restricted profiles. Circuit-specific and adaptive expression of neuropeptide genes may be defined by transcriptional and epigenetic mechanisms controlled by cell type and subtype sequence-specific transcription factors, insulators and silencers. The opioid peptide dynorphins play a critical role in neurological and psychiatric disorders, pain processing and stress, while their mutations cause profound neurodegeneration in the human brain. In this review, we focus on the prodynorphin gene as a model for the in-depth epigenetic and transcriptional analysis of expression of the neuropeptide genes. Prodynorphin studies may provide a framework for analysis of mechanisms relevant for regulation of neuropeptide genes in normal and pathological human brain.


Assuntos
Encéfalo/metabolismo , Encefalinas/genética , Epigênese Genética/genética , Precursores de Proteínas/genética , Transcrição Genética/genética , Analgésicos Opioides/metabolismo , Animais , Epigenômica/métodos , Regulação da Expressão Gênica/genética , Humanos , Neuropeptídeos/genética
13.
Int J Mol Sci ; 22(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198907

RESUMO

Melanogenesis is the process leading to the synthesis of melanin, the main substance that influences skin color and plays a pivotal role against UV damage. Altered melanogenesis is observed in several pigmentation disorders. Melanogenesis occurs in specialized cells called melanocytes, physically and functionally related by means of autocrine and paracrine interplay to other skin cell types. Several external and internal factors control melanin biosynthesis and operate through different intracellular signaling pathways, which finally leads to the regulation of microphthalmia-associated transcription factor (MITF), the key transcription factor involved in melanogenesis and the expression of the main melanogenic enzymes, including TYR, TYRP-1, and TYRP-2. Epigenetic factors, including microRNAs (miRNAs), are involved in melanogenesis regulation. miRNAs are small, single-stranded, non-coding RNAs, of approximately 22 nucleotides in length, which control cell behavior by regulating gene expression, mainly by binding the 3' untranslated region (3'-UTR) of target mRNAs. This review collects data on the miRNAs involved in melanogenesis and how these miRNAs can modulate target gene expression. Bringing to light the biological function of miRNAs could lead to a wider understanding of epigenetic melanogenesis regulation and its dysregulation. This knowledge may constitute the basis for developing innovative treatment approaches for pigmentation dysregulation.


Assuntos
Melaninas/biossíntese , MicroRNAs/genética , Transtornos da Pigmentação/genética , Pigmentação da Pele/genética , Animais , Epigênese Genética/genética , Regulação da Expressão Gênica/genética , Humanos , Melaninas/genética , Melanócitos/metabolismo , Fator de Transcrição Associado à Microftalmia/genética , Transtornos da Pigmentação/patologia
14.
Int J Mol Sci ; 22(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34298921

RESUMO

Chronic inflammation is considered to be a silent killer because it is the underlying cause of a wide range of clinical disorders, from cardiovascular to neurological diseases, and from cancer to obesity. In addition, there are over 80 different types of debilitating autoimmune diseases for which there are no cure. Currently, the drugs that are available to suppress chronic inflammation are either ineffective or overtly suppress the inflammation, thereby causing increased susceptibility to infections and cancer. Thus, the development of a new class of drugs that can suppress chronic inflammation is imperative. Cannabinoids are a group of compounds produced in the body (endocannabinoids) or found in cannabis (phytocannabinoids) that act through cannabinoid receptors and various other receptors expressed widely in the brain and immune system. In the last decade, cannabinoids have been well established experimentally to mediate anti-inflammatory properties. Research has shown that they suppress inflammation through multiple pathways, including apoptosis and inducing immunosuppressive T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Interestingly, cannabinoids also mediate epigenetic alterations in genes that regulate inflammation. In the current review, we highlight how the epigenetic modulations caused by cannabinoids lead to the suppression of inflammation and help identify novel pathways that can be used to target autoimmune diseases.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/genética , Canabinoides/farmacologia , Epigênese Genética/genética , Inflamação/tratamento farmacológico , Inflamação/genética , Animais , Humanos , Sistema Imunitário/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos
15.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203452

RESUMO

Adipokines secreted by hypertrophic visceral adipose tissue (VAT) instigate low-grade inflammation, followed by hyperglycemia (HG)-related metabolic disorders. The latter may develop with the participation of epigenetic modifications. Our aim was to assess how HG influences selected epigenetic modifications and the expression of interleukin 6 (IL-6) and adiponectin (APN; gene symbol ADIPOQ) during the adipogenesis of human visceral preadipocytes (HPA-v). Adipocytes (Ads) were chronically or transiently HG-treated during three stages of adipogenesis (proliferation, differentiation, maturation). We measured adipokine mRNA, protein, proven or predicted microRNA expression (RT-qPCR and ELISA), and enrichment of H3K9/14ac, H3K4me3, and H3K9me3 at gene promoter regions (chromatin immunoprecipitation). In chronic HG, we detected different expression patterns of the studied adipokines at the mRNA and protein levels. Chronic and transient HG-induced changes in miRNA (miR-26a-5p, miR-26b-5p, let-7d-5p, let-7e-5p, miR-365a-3p, miR-146a-5p) were mostly convergent to altered IL-6 transcription. Alterations in histone marks at the IL6 promoter were also in agreement with IL-6 mRNA. The open chromatin marks at the ADIPOQ promoter mostly reflected the APN transcription during NG adipogenesis, while, in the differentiation stage, HG-induced changes in all studied marks were in line with APN mRNA levels. In summary, HG dysregulated adipokine expression, promoting inflammation. Epigenetic changes coexisted with altered expression of adipokines, especially for IL-6; therefore, epigenetic marks induced by transient HG may act as epi-memory in Ads. Such changes in the epigenome and expression of adipokines could be instrumental in the development of inflammation and metabolic deregulation of VAT.


Assuntos
Adipócitos/metabolismo , Adiponectina/metabolismo , Hiperglicemia/metabolismo , Regiões Promotoras Genéticas/genética , Adipogenia/genética , Adipogenia/fisiologia , Adiponectina/genética , Imunoprecipitação da Cromatina , Ensaio de Imunoadsorção Enzimática , Epigênese Genética/genética , Epigênese Genética/fisiologia , Humanos , Hiperglicemia/genética , Interleucina-6/metabolismo
17.
Nat Commun ; 12(1): 4273, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34257309

RESUMO

Genes with identical DNA sequence may show differential expression because of epigenetic marks. Where epigenetic marks respond to past conditions, they represent a form of "memory". Despite their medical relevance, the impact of memories on the evolution of infectious diseases has rarely been considered. Here we explore the evolution of virulence in pathogens that carry memories of the sex of their previous host. We show that this form of memory provides information about the sex of present and future hosts when the sexes differ in their pathogen's transmission pattern. Memories of past hosts enable the evolution of greater virulence in infections originating from one sex and infections transmitted across sexes. Thus, our results account for patterns of virulence that have, to date, defied medical explanation. In particular, it has been observed that girls infected by boys (or boys infected by girls) are more likely to die from measles, chickenpox and polio than girls infected by girls (or boys infected by boys). We also evaluate epigenetic therapies that tamper with the memories of infecting pathogens. More broadly, our findings imply that pathogens can be selected to carry memories of past environments other than sex. This identifies new directions in personalised medicine.


Assuntos
Doenças Transmissíveis/genética , Epigênese Genética/genética , Animais , Humanos , Memória/fisiologia , Virulência/genética , Virulência/fisiologia
18.
Eur J Med Chem ; 222: 113588, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34107385

RESUMO

Abnormal epigenetics is a critical hallmark of human cancers. Anticancer drug discovery directed at histone epigenetic modulators has gained impressive advances with six drugs available for cancer therapy and numerous other candidates undergoing clinical trials. However, limited therapeutic profile, drug resistance, narrow safety margin, and dose-limiting toxicities pose intractable challenges for their clinical utility. Because histone epigenetic modulators undergo intricate crosstalk and act cooperatively to shape an aberrant epigenetic profile, co-targeting histone epigenetic modulators with a different mechanism of action has rapidly emerged as an attractive strategy to overcome the limitations faced by the single-target epigenetic inhibitors. In this review, we summarize in detail the crosstalk of histone epigenetic modulators in regulating gene transcription and the progress of dual epigenetic inhibitors targeting this crosstalk.


Assuntos
Antineoplásicos/farmacologia , Epigênese Genética/efeitos dos fármacos , Histonas/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Epigênese Genética/genética , Histonas/genética , Humanos , Estrutura Molecular , Neoplasias/genética
19.
Commun Biol ; 4(1): 642, 2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-34059764

RESUMO

The development of a precise blood or skin tissue DNA Epigenetic Aging Clock for Odontocete (OEAC) would solve current age estimation inaccuracies for wild odontocetes. Therefore, we determined genome-wide DNA methylation profiles using a custom array (HorvathMammalMethyl40) across skin and blood samples (n = 446) from known age animals representing nine odontocete species within 4 phylogenetic families to identify age associated CG dinucleotides (CpGs). The top CpGs were used to create a cross-validated OEAC clock which was highly correlated for individuals (r = 0.94) and for unique species (median r = 0.93). Finally, we applied the OEAC for estimating the age and sex of 22 wild Norwegian killer whales. DNA methylation patterns of age associated CpGs are highly conserved across odontocetes. These similarities allowed us to develop an odontocete epigenetic aging clock (OEAC) which can be used for species conservation efforts by provide a mechanism for estimating the age of free ranging odontocetes from either blood or skin samples.


Assuntos
Envelhecimento/genética , Golfinhos/metabolismo , Baleias/metabolismo , Fatores Etários , Envelhecimento/fisiologia , Animais , DNA/genética , Metilação de DNA/genética , Golfinhos/genética , Epigênese Genética/genética , Epigenômica/métodos , Genoma , Filogenia , Baleias/genética
20.
Mutat Res Rev Mutat Res ; 787: 108370, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34083045

RESUMO

Despite being an important diagnostic and treatment modality, ionizing radiation (IR) is also known to cause genotoxicity and multiple side effects leading to secondary carcinogenesis. While modern cancer radiation therapy has improved patient recovery and enhanced survival rates, the risk of radiation-related adverse effects has become a growing challenge. It is now well-accepted that IR-induced side effects are not exclusively restricted to exposed cells but also spread to distant 'bystander' cells and even to the unexposed progeny of the irradiated cells. These 'off-targeted' effects involve a plethora of molecular events depending on the type of radiation and tumor tissue background. While the mechanisms by which off-targeted effects arise remain obscure, emerging evidence based on the non-mendelian inheritance of various manifestations of them as well as their persistence for longer periods supports a contribution of epigenetic factors. This review focuses on the major epigenetic phenomena including DNA methylation, histone modifications, and small RNA mediated silencing and their versatile role in the manifestation of IR induced off-targeted effects. As short- and long-range communication vehicles respectively, the role of gap junctions and exosomes in spreading these epigenetic-alteration driven off-targeted effects is also discussed. Furthermore, this review emphasizes the possible therapeutic potentials of these epigenetic mechanisms and how beneficial outcomes could potentially be achieved by targeting various signaling molecules involved in these mechanisms.


Assuntos
Epigênese Genética/genética , Efeito Espectador/genética , Efeito Espectador/fisiologia , Metilação de DNA/genética , Metilação de DNA/fisiologia , Instabilidade Genômica/genética , Instabilidade Genômica/fisiologia , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo
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