RESUMO
Adverse conditions in early life, including environmental, biological and social influences, are risk factors for ill-health during aging and the onset of age-related disorders. In this context, the recent field of social epigenetics offers a valuable method for establishing the relationships among them However, current clinical studies on environmental changes and lifespan disorders are limited. In this sense, the Tlaltizapan (Mexico) cohort, who 52 years ago was exposed to infant malnutrition, low income and poor hygiene conditions, represents a vital source for exploring such factors. Therefore, in the present study, 52 years later, we aimed to explore differences in clinical/biochemical/anthropometric and epigenetic (DNA methylation) variables between individuals from such a cohort, in comparison with an urban-raised sample. Interestingly, only cholesterol levels showed significant differences between the cohorts. On the other hand, individuals from the Tlaltizapan cohort with more years of schooling had a lower epigenetic age in the Horvath (p-value = 0.0225) and PhenoAge (p-value = 0.0353) clocks, compared to those with lower-level schooling. Our analysis indicates 12 differentially methylated sites associated with the PI3-Akt signaling pathway and galactose metabolism in individuals with different durations of schooling. In conclusion, our results suggest that longer durations of schooling could promote DNA methylation changes that may reduce epigenetic age; nevertheless, further studies are needed.
Assuntos
Envelhecimento , Escolaridade , Epigênese Genética/fisiologia , Aprendizagem/fisiologia , Determinantes Sociais da Saúde , Envelhecimento/genética , Envelhecimento/psicologia , Estudos de Coortes , Metilação de DNA , Feminino , Interação Gene-Ambiente , Humanos , Recém-Nascido , Longevidade/genética , Estudos Longitudinais , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Instituições AcadêmicasRESUMO
Gestational diabetes mellitus (GDM) is the most common metabolic complication in pregnancy, which affects the future health of both the mother and the newborn. Its pathophysiology involves nutritional, hormonal, immunological, genetic and epigenetic factors. Among the latter, it has been observed that alterations in DNA (deoxyribonucleic acid) methylation patterns and in the levels of certain micro RNAs, whether in placenta or adipose tissue, are related to well-known characteristics of the disease, such as hyperglycemia, insulin resistance, inflammation and excessive placental growth. Furthermore, epigenetic alterations of gestational diabetes mellitus are observable in maternal blood, although their pathophysiological roles are completely unknown. Despite this, it has not been possible to determine the causes of the epigenetic characteristics of GDM, highlighting the need for integral and longitudinal studies. Based on this, this article summarizes the most relevant and recent studies on epigenetic alterations in placenta, adipose tissue and maternal blood associated with GDM in order to provide the reader with a general overview of the subject and indicate future research topics.
Assuntos
Diabetes Gestacional/genética , Epigênese Genética/genética , Tecido Adiposo/metabolismo , DNA/química , Metilação de DNA/genética , Diabetes Gestacional/metabolismo , Epigênese Genética/fisiologia , Epigenômica/métodos , Feminino , Humanos , MicroRNAs/genética , Placenta/metabolismo , Gravidez , GestantesRESUMO
Adverse childhood experiences (ACEs) are associated with a high risk of developing chronic diseases and decreased life expectancy, but no ACE epigenetic biomarkers have been identified until now. The latter may result from the interaction of multiple factors such as age, sex, degree of adversity, and lack of transcriptional effects of DNA methylation changes. We hypothesize that DNA methylation changes are related to childhood adversity levels and current age, and these markers evolve as aging proceeds. Two Gene Expression Omnibus datasets, regarding ACE, were selected (GSE72680 and GSE70603), considering raw- and meta-data availability, including validated ACE index (Childhood Trauma Questionnaire (CTQ) score). For DNA methylation, analyzed probes were restricted to those laying within promoters and first exons, and samples were grouped by CTQ scores terciles, to compare highly (ACE) with non-abused (control) cases. Comparison of control and ACE methylome profile did not retrieve differentially methylated CpG sites (DMCs) after correcting by false discovery rate < 0.05, and this was also observed when samples were separated by sex. In contrast, grouping by decade age ranges (i.e., the 20s, 30s, 40s, and 50s) showed a progressive increase in the number of DMCs and the intensity of changes, mainly related with hypomethylation. Comparison with transcriptome data for ACE subjects in the 40s, and 50s showed a similar age-dependent effect. This study provides evidence that epigenetic markers of ACE are age-dependent, but not defined in the long term. These differences among early, middle, and late adulthood epigenomic profiles suggest a window for interventions aimed to prevent the detrimental effects of ACE.
Assuntos
Experiências Adversas da Infância/classificação , Envelhecimento/psicologia , Metilação de DNA/fisiologia , Fatores de Tempo , Adulto , Epigênese Genética/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Heterozygous chromosomal rearrangements can result in failures during the meiotic cycle and the apoptosis of germline, making carrier individuals infertile. The Amazon frog Leptodactylus pentadactylus has a meiotic multivalent, composed of 12 sex chromosomes. The mechanisms by which this multi-chromosome system maintains fertility in males of this species remain undetermined. In this study we investigated the meiotic behavior of this multivalent to understand how synapse, recombination and epigenetic modifications contribute to maintaining fertility and chromosomal sexual determination in this species. Our sample had 2n = 22, with a ring formed by ten chromosomes in meiosis, indicating a new system of sex determination for this species (X1Y1X2Y2X3Y3X4Y4X5Y5). Synapsis occurs in the homologous terminal portion of the chromosomes, while part of the heterologous interstitial regions performed synaptic adjustment. The multivalent center remains asynaptic until the end of pachytene, with interlocks, gaps and rich-chromatin in histone H2A phosphorylation at serine 139 (γH2AX), suggesting transcriptional silence. In late pachytene, paired regions show repair of double strand-breaks (DSBs) with RAD51 homolog 1 (Rad51). These findings suggest that Rad51 persistence creates positive feedback at the pachytene checkpoint, allowing meiosis I to progress normally. Additionally, histone H3 trimethylation at lysine 27 in the pericentromeric heterochromatin of this anuran can suppress recombination in this region, preventing failed chromosomal segregation. Taken together, these results indicate that these meiotic adaptations are required for maintenance of fertility in L. pentadactylus.
Assuntos
Anuros/genética , Animais , Anuros/fisiologia , Análise Citogenética , Epigênese Genética/genética , Epigênese Genética/fisiologia , Fertilidade/genética , Fertilidade/fisiologia , Rearranjo Gênico/genética , Rearranjo Gênico/fisiologia , Masculino , Meiose , Cromossomos Sexuais/genéticaAssuntos
Transdiferenciação Celular , Imunoterapia/efeitos adversos , Linfoma de Célula do Manto/terapia , Segunda Neoplasia Primária/etiologia , Sarcoma/etiologia , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transdiferenciação Celular/genética , Transdiferenciação Celular/imunologia , Reprogramação Celular/genética , Reprogramação Celular/imunologia , Reprogramação Celular/fisiologia , Terapia Combinada , Epigênese Genética/fisiologia , Epigenoma/imunologia , Rearranjo Gênico , Genes de Cadeia Pesada de Imunoglobulina/genética , Humanos , Imunoterapia/métodos , Linfonodos/patologia , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/imunologia , Segunda Neoplasia Primária/diagnóstico , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Receptores de Antígenos de Linfócitos T/uso terapêutico , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Sarcoma/genética , Sarcoma/imunologia , Sarcoma/patologia , Transplante Autólogo/efeitos adversos , Células Tumorais CultivadasRESUMO
Many sex differences in liver gene expression originate in the brain, depend on GH secretion and may underlie sex disparities in hepatic disease. Because epigenetic mechanisms may contribute, we studied promoter methylation and microRNA abundance in the liver, associated with expression of sexual dimorphic genes in mice with selective disruption of the dopamine D2 receptor in neurons (neuroDrd2KO), which decreases hypothalamic Ghrh, pituitary GH, and serum IGFI and in neonatally androgenized female mice which have increased pituitary GH content and serum IGFI. We evaluated mRNA levels of the female predominant genes prolactin receptor (Prlr), alcohol dehydrogenase 1 (Adh1), Cyp2a4, and hepatocyte nuclear transcription factor 6 (Hnf6) and the male predominant gene, Cyp7b1. Female predominant genes had higher mRNA levels compared to males, but lower methylation was only detected in the Prlr and Cyp2a4 female promoters. In neuroDrd2KO mice, sexual dimorphism was lost for all genes; the upregulation (feminization) of Prlr and Cyp2a4 in males correlated with decreased methylation of their promoters, and the downregulation (masculinization) of Hnf-6 mRNA in females correlated inversely with its promoter methylation. Neonatal androgenization of females evoked a loss of sexual dimorphism only for the female predominant Hnf6 and Adh1 genes, but no differences in promoter methylation were found. Finally, mmu-miR-155-5p, predicted to target Cyp7b1 expression, was lower in males in association with higher Cyp7b1 mRNA levels compared to females and was not modified in neuroDrd2KO or TP mice. Our results suggest specific regulation of gene sexually dimorphic expression in the liver by methylation or miRNAs.
Assuntos
Álcool Desidrogenase/genética , Hidrocarboneto de Aril Hidroxilases/genética , Família 2 do Citocromo P450/genética , Família 7 do Citocromo P450/genética , Hormônio do Crescimento/farmacologia , Fator 6 Nuclear de Hepatócito/genética , Receptores da Prolactina/genética , Esteroide Hidroxilases/genética , Álcool Desidrogenase/metabolismo , Animais , Hidrocarboneto de Aril Hidroxilases/metabolismo , Família 2 do Citocromo P450/metabolismo , Família 7 do Citocromo P450/metabolismo , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/fisiologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônio do Crescimento/metabolismo , Fator 6 Nuclear de Hepatócito/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Regiões Promotoras Genéticas/genética , Receptores da Prolactina/metabolismo , Caracteres Sexuais , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Esteroide Hidroxilases/metabolismoRESUMO
The pedunculopontine nucleus (PPN) is part of the reticular activating system (RAS) in charge of arousal and rapid eye movement sleep. The presence of high-frequency membrane oscillations in the gamma-band range in the PPN has been extensively demonstrated both in vivo and in vitro. Our group previously described histone deacetylation (HDAC) inhibition in vitro induced protein changes in F-actin cytoskeleton and intracellular Ca2+ concentration regulation proteins in the PPN. Here, we present evidence that supports the presence of a fine balance between HDAC function and calcium calmodulin kinase II-F-actin interactions in the PPN. We modified F-actin polymerization in vitro by using jasplakinolide (1 µM, a promoter of F-actin stabilization), or latrunculin-B (1 µM, an inhibitor of actin polymerization). Our results showed that shifting the balance in either direction significantly reduced PPN gamma oscillation as well as voltage-dependent calcium currents.
Assuntos
Actinas/metabolismo , Epigênese Genética/fisiologia , Neurônios/metabolismo , Núcleo Tegmental Pedunculopontino/metabolismo , Citoesqueleto de Actina/metabolismo , Animais , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Epigênese Genética/genética , Feminino , Masculino , Potenciais da Membrana/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
Spermatogenesis is characterized by unique epigenetic programs that enable chromatin remodeling and transcriptional regulation for proper meiotic divisions and germ cells maturation. Paternal lifestyle stressors such as diet, drug abuse, or psychological trauma can directly impact the germ cell epigenome and transmit phenotypes to the next generation, pointing to the importance of epigenetic regulation during spermatogenesis. It is established that environmental perturbations can affect the development and behavior of the offspring through epigenetic inheritance, including changes in small non-coding RNAs, DNA methylation, and histones post-translational modifications. But how male germ cells react to lifestyle stressors and encode them in the paternal epigenome is still a research gap. Most lifestyle stressors activate catecholamine circuits leading to both acute and long-term changes in neural functions, and epigenetic mechanisms show strong links to both long-term and rapid, dynamic gene expression regulation during stress. Importantly, the testis shares a molecular and transcriptional signature with the brain tissue, including a rich expression of catecholaminergic elements in germ cells that seem to respond to stressors with similar epigenetic and transcriptional profiles. In this minireview, we put on stage the action of catecholamines as possible mediators between paternal stress responses and epigenetic marks alterations during spermatogenesis. Understanding the epigenetic regulation in spermatogenesis will contribute to unravel the coding mechanisms in the transmission of the biological impacts of stress between generations.
Assuntos
Catecolaminas/metabolismo , Epigênese Genética/fisiologia , Células Germinativas/metabolismo , Estresse Oxidativo/fisiologia , Espermatogênese/fisiologia , Estresse Psicológico/metabolismo , Animais , Catecolaminas/genética , Células Germinativas/patologia , Humanos , Masculino , Estresse Psicológico/genética , Estresse Psicológico/patologiaRESUMO
Understanding preimplantation embryonic development is crucial for the improvement of assisted reproductive technologies and animal production. To achieve this goal, it is important to consider that gametes and embryos are highly susceptible to environmental changes. Beyond the metabolic adaptation, the dynamic status imposed during follicular growth and early embryogenesis may create marks that will guide the molecular regulation during prenatal development, and consequently impact the offspring phenotype. In this context, metaboloepigenetics has gained attention, as it investigates the crosstalk between metabolism and molecular control, i.e., how substrates generated by metabolic pathways may also act as players of epigenetic modifications. In this review, we present the main metabolic and epigenetic events of pre-implantation development, and how these systems connect to open possibilities for targeted manipulation of reproductive technologies and animal production systems.
Assuntos
Animais , Desenvolvimento Embrionário , Epigênese Genética/fisiologia , Implantação do EmbriãoRESUMO
Understanding preimplantation embryonic development is crucial for the improvement of assisted reproductive technologies and animal production. To achieve this goal, it is important to consider that gametes and embryos are highly susceptible to environmental changes. Beyond the metabolic adaptation, the dynamic status imposed during follicular growth and early embryogenesis may create marks that will guide the molecular regulation during prenatal development, and consequently impact the offspring phenotype. In this context, metaboloepigenetics has gained attention, as it investigates the crosstalk between metabolism and molecular control, i.e., how substrates generated by metabolic pathways may also act as players of epigenetic modifications. In this review, we present the main metabolic and epigenetic events of pre-implantation development, and how these systems connect to open possibilities for targeted manipulation of reproductive technologies and animal production systems.(AU)