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1.
Ideggyogy Sz ; 72(9-10): 325-336, 2019 Sep 30.
Artigo em Húngaro | MEDLINE | ID: mdl-31625699

RESUMO

With the acceptance of "The developmental origins of health and disease" concept in the 1990s, it became clear that epigenetic inheritance, which do not involve changes in the DNA sequence has important role in the pathogenesis of diseases. Epigenetic regulation serves the adaptation to the changing environment and maintains the reproductive fitness even on the drawback of increased risk of diseases in later life. The role of epigenetic mechanisms in chronic non-communicable diseases has been well established. Recent studies have revealed that epigenetic changes have also causal role in certain pediatric diseases. The review evaluates the recent epigenetic findings in the pathomechanism of common pediatric diseases. The wide range and long-lasting duration of epigenetic regulations give importance to the subject. Methods are already available to evaluate a part of the epigenetic changes in the clinical practice, presently aiming primarily the estimation of the disease risk or definition of diagnosis. Furthermore, there are already available limited means to influence the epigenetic regulation.


Assuntos
Metilação de DNA/fisiologia , Epigênese Genética , Cardiopatias , Infecção , Transtornos Mentais , Doenças Metabólicas , Efeitos Tardios da Exposição Pré-Natal , Criança , Pré-Escolar , Metilação de DNA/genética , Feminino , Cardiopatias/genética , Humanos , Infecção/genética , Transtornos Mentais/genética , Doenças Metabólicas/genética , Pediatria , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética
3.
Gene ; 718: 144049, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31430520

RESUMO

The role of epigenetics in development has garnered attention in recent years due to their ability to modulate the embryonic developmental gene expression in response to the environmental cues. The epigenetic mechanisms - DNA methylation, histone modification, and non-coding RNAs have a unique impact on vertebrate development. Zebrafish, a model vertebrate organism is being used widely in developmental studies due to their high fecundability and rapid organogenesis. With increased studies on various aspects of epigenetics in development, this review gives a glimpse of the major epigenetic modifications and their role in zebrafish development. In this review, the basic mechanism behind each modification followed by their status in zebrafish has been reviewed. Further, recent advancements in the epigenetic aspect of zebrafish development have been discussed.


Assuntos
Metilação de DNA/fisiologia , Embrião não Mamífero/embriologia , Desenvolvimento Embrionário/fisiologia , Epigênese Genética/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Peixe-Zebra/embriologia , Animais , Histonas/genética , Histonas/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Peixe-Zebra/genética
4.
Gene ; 718: 144018, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31454543

RESUMO

Cytosine DNA methylation (5mC) is an epigenetic mark that regulates gene expression in plant responses to environmental stresses. Zinc-finger protein (ZFP) is the largest family of DNA-binding transcription factors that also plays an essential role in eukaryote. In plant we have already identified and characterized different useful ZFP-genes. While, the main objective of this research was to observe and identify more targeted stress responsive genes of ZFPs epigenetically throughout genome in rice for the first time. A comprehensive correlation analysis was performed through methylated DNA immunoprecipitation (MeDIP)-chip hybridization in rice under salt and osmotic stresses. High salinity and drought are two major abiotic hazards that are destroying the crop world-wide. As a result, Through-out genome 14 unique stress responsive transcription factors of ZFP-genes with varying level of methylation and expression under two conditions (control vs. stress) were isolated. All the identified genes were confirmed from different databases for their specific structure, cis-regulatory elements, phylogenetic analysis, and synteny analysis. Moreover, the tissue-specific expression patterns, and expression under abiotic and phytohormones stresses were also investigated. Phylogenetically all the genes were divided into 6 distinct subgroups with Arabidopsis and orthologous proteins were find-out through synteny analysis. Available RNA-seq data in response to various phytohormones provided hormone inducible gene expression profile. Through Reverse Transcriptase qPCR (RT-qPCR) analysis tissue-specific expression in shoot and root over various time points against salt and osmotic stresses exhibited the diverse expression patterns of identified genes. Overall, the present study providing a foundation for in-depth characterization of identified genes and to further understand the epigenetic role of DNA methylation for genes expression and environmental stresses regulation in higher plant.


Assuntos
Metilação de DNA/fisiologia , DNA de Plantas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas/fisiologia , Oryza , Proteínas de Plantas , Estresse Fisiológico/fisiologia , Fatores de Transcrição , DNA de Plantas/genética , DNA de Plantas/metabolismo , Estudo de Associação Genômica Ampla , Oryza/genética , Oryza/metabolismo , Proteínas de Plantas/classificação , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Fatores de Transcrição/classificação , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
5.
Nat Commun ; 10(1): 2999, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278262

RESUMO

The different genome-wide distributions of tri-methylation at H3K36 (H3K36me3) in various species suggest diverse mechanisms for H3K36me3 establishment during evolution. Here, we show that the transcription factor OsSUF4 recognizes a specific 7-bp DNA element, broadly distributes throughout the rice genome, and recruits the H3K36 methyltransferase SDG725 to target a set of genes including the key florigen genes RFT1 and Hd3a to promote flowering in rice. Biochemical and structural analyses indicate that several positive residues within the zinc finger domain are vital for OsSUF4 function in planta. Our results reveal a regulatory mechanism contributing to H3K36me3 distribution in plants.


Assuntos
Histona-Lisina N-Metiltransferase/metabolismo , Histonas/genética , Oryza/fisiologia , Proteínas de Plantas/metabolismo , Transativadores/metabolismo , Metilação de DNA/fisiologia , Flores/crescimento & desenvolvimento , Regulação da Expressão Gênica de Plantas/fisiologia , Regiões Promotoras Genéticas/genética , Ligação Proteica/genética
6.
Nat Commun ; 10(1): 3053, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311924

RESUMO

The germline is the only cellular lineage capable of transferring genetic information from one generation to the next. Intergenerational transmission of epigenetic memory through the germline, in the form of DNA methylation, has been proposed; however, in mammals this is largely prevented by extensive epigenetic erasure during germline definition. Here we report that, unlike mammals, the continuously-defined 'preformed' germline of zebrafish does not undergo genome-wide erasure of DNA methylation during development. Our analysis also uncovers oocyte-specific germline amplification and demethylation of an 11.5-kb repeat region encoding 45S ribosomal RNA (fem-rDNA). The peak of fem-rDNA amplification coincides with the initial expansion of stage IB oocytes, the poly-nucleolar cell type responsible for zebrafish feminisation. Given that fem-rDNA overlaps with the only zebrafish locus identified thus far as sex-linked, we hypothesise fem-rDNA expansion could be intrinsic to sex determination in this species.


Assuntos
Metilação de DNA/fisiologia , DNA Ribossômico/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Oócitos/metabolismo , Peixe-Zebra/fisiologia , Animais , Desmetilação , Epigênese Genética/fisiologia , Feminino , Masculino , RNA Ribossômico/genética , Caracteres Sexuais
7.
J Cancer Res Clin Oncol ; 145(8): 1939-1948, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31263949

RESUMO

OBJECTIVE: Some studies have shown that the methylation status of the GSTP1 gene promoter is related to the incidence of prostate cancer, but this finding is still controversial. The aim of this study was to evaluate the association between glutathione-S-transferase p1 (GSTP1) promoter methylation and the incidence of prostate cancer. METHODS: The Medline, Embase, Web of Science, and Cochrane CENTRAL databases were searched from their inception to February 22, 2019. According to the inclusion criteria, studies of the association between the methylation status of the GSTP1 gene promoter and prostate cancer were included. The difference in the incidence of GSTP1 promoter methylation in tissues, blood, or urine between patients with prostate cancer and those without prostate cancer were compared, and the results were expressed as the odds ratio (OR) and 95% confidence interval (CI). The pooled OR of each study was estimated using a fixed-effects model or a random-effects model to generate forest plots. RESULTS: Ultimately, 15 studies (1540 samples) were included. The estimated effect from our meta-analysis showed that the incidence of GSTP1 promoter methylation was higher in patients with prostate cancer than in those without prostate cancer (OR 18.58, 95% CI 9.60-35.95, P = 0.000). GSTP1 promoter methylation was highly correlated with the incidence of prostate cancer. CONCLUSIONS: Methylation of the GSTP1 promoter may increase the risk of prostate cancer. This study may provide a strategic direction for prostate cancer research. Pending validation of these findings, the methylation of the GSTP1 promoter may be a potential biomarker to diagnose prostate cancer.


Assuntos
Biomarcadores Tumorais/genética , Metilação de DNA/fisiologia , Glutationa S-Transferase pi/genética , Regiões Promotoras Genéticas , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Humanos , Incidência , Masculino , Neoplasias da Próstata/genética
8.
Nurs Outlook ; 67(4): 337-344, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31248628

RESUMO

BACKGROUND: A rapidly expanding literature suggests that individuals of the same chronological age show significant variation in biological age. PURPOSE: The purpose of this article is to review the literature surrounding epigenetic age as estimated by DNA methylation, involving the addition or removal of methyl groups to DNA that can alter gene expression without changing the DNA sequence. METHODS: This state of the science literature review summarizes current approaches in epigenetic age determination and applications of aging algorithms. FINDINGS: A number of algorithms estimate epigenetic age using DNA methylation markers, primarily among adults. Algorithm application has focused on determining predictive value for risk of disease and death and identifying antecedents to age acceleration. Several studies have incorporated epigenetic age to evaluate intervention effectiveness. DISCUSSION: As the research community continues to refine aging algorithms, there may be opportunity to promote health from a precision health perspective.


Assuntos
Envelhecimento/genética , Envelhecimento/fisiologia , Metilação de DNA/fisiologia , Epigênese Genética/genética , Marcadores Genéticos/fisiologia , Promoção da Saúde/métodos , Medicina de Precisão/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Nat Commun ; 10(1): 2581, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197173

RESUMO

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.


Assuntos
Metilação de DNA/fisiologia , Diabetes Mellitus Tipo 2/genética , Glucose/metabolismo , Insulina/metabolismo , Obesidade/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Simulação por Computador , Ilhas de CpG/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigênese Genética/fisiologia , Epigenômica/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Homeostase/genética , Humanos , Masculino , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Obesidade/metabolismo , Polimorfismo de Nucleotídeo Único/fisiologia , Adulto Jovem
10.
Biol Res ; 52(1): 31, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182157

RESUMO

BACKGROUND: The purpose of the present study was to investigate the role of the methylation status of the DACT1 gene on the invasion and metastasis of nasopharyngeal carcinoma cells. METHODS: The levels of methylation and expression of the DACT1 gene in nasopharyngeal carcinoma tissues and CNE2 cells were determined by methylation-specific PCR and RT-PCR, respectively. CNE2 cells were treated with 5-aza-2-deoxycytidine, and the variation in the methylation status of the DACT1 gene was detected, as well as the influence of methylation on invasiveness of nasopharyngeal carcinoma cells. RESULTS: The DACT1 gene was hyper-methylated in 44 of 62 cases of nasopharyngeal carcinoma. The DACT1 gene was hyper-methylated in 32 of 38 cases of nasopharyngeal carcinoma with lymph node metastasis, and the DACT1 gene was hyper-methylated in 7 of 24 cases of nasopharyngeal carcinoma without lymph node metastasis. The DACT1 mRNA level was weakly expressed or not expressed in all nasopharyngeal carcinoma tissues with hyper-methylated DACT1 genes; however, the DACT1 mRNA level was highly expressed in nasopharyngeal carcinoma tissues with low expression of the methylated DACT1 gene. The DACT1 gene was hyper-methylated and not expressed in CNE2 cells that did not have 5-aza-2-deoxycytidine treatment. After 5-aza-2-deoxycytidine treatment, the DACT1 gene was demethylated and the expression of DACT1 was restored. Moreover, the invasion ability was inhibited in CNE2 cells treated with 5-aza-2-deoxycytidine. CONCLUSION: The expression of DACT1 was related to the methylation status. High expression of DACT1 may inhibit the invasion and metastasis of nasopharyngeal carcinoma cells.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Metilação de DNA/genética , Carcinoma Nasofaríngeo/secundário , Neoplasias Nasofaríngeas/patologia , Proteínas Nucleares/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Metilação de DNA/fisiologia , Feminino , Humanos , Masculino , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Invasividade Neoplásica , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas
11.
J Plant Physiol ; 239: 18-27, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31177027

RESUMO

DNA methylation is a process of epigenetic modification that can alter the functionality of a genome. Using whole-genome bisulfite sequencing, this study quantify the level of DNA methylation in the epigenomes of two diploid apple (Malus x domestica) scion cultivars ('McIntosh' and 'Húsvéti rozmaring') derived from three environmental conditions: in vivo mother plants in an orchard, in vitro culture, and acclimatized in vitro plants. The global DNA methylation levels were not dependent on the source of plant material, and the average level of DNA methylation was 49.77%, 34.65% and 8.77% in CpG, CHG and CHH contexts, respectively. Significant differences in DNA methylation were identified in 586 (specifically 334, 201 and 131 in CpG, CHG and CHH contexts, respectively) out of 45,116 genes, including promoter and coding sequences. These were classified as differentially methylated genes (DMGs). This is a 1.3% difference in the level of DNA methylation of genes in response to a change in the environment. Differential methylation was visualised by MA plots and functional genomic maps were established for biological processes, molecular functions and cellular components. When the DMGs were considered, in vitro tissue culture resulted in the highest level of methylation, but it was lower in acclimatized in vitro plants which was similar to that in the mother tree. Methylation patterns of the two scions differed, indicating cultivar-specific epigenetic regulation of gene expression during adaptation to various environments. After selecting genes that displayed differences larger than ±10% in CpG and CHG contexts, or larger than ±1.35% in the CHH context from among the DMGs, they were annotated in Blast2 GO v5.1.12 for Gene Ontology. DMGs identified as MD07G1113000 (protein transport), MD08G1041600 (extracellular space), MD09G1054800 (phosphatidic acid binding), and MD10G1265800 (not annotated) were methylated in all three contexts in in vitro shoots. These DNA methylation results suggest that epigenetic changes may contribute to the adaptation of apple to environmental changes by modifying the epigenome and thereby gene expression.


Assuntos
Aclimatação , Metilação de DNA/fisiologia , Genoma de Planta , Malus/genética , Técnicas de Cultura de Células , Epigênese Genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Brotos de Planta/metabolismo
12.
Plant Cell Physiol ; 60(8): 1702-1721, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31077318

RESUMO

In plants, DNA methylation (i.e. chromatin modification) is important for various biological processes, including growth, development and flowering. Because 'Fuji' apple trees are alternate bearing and have a long ripening period and poor-quality flower buds, we used bud types with diverse flowering capabilities to investigate the epigenetic regulatory mechanisms influencing flower bud formation. We examined the DNA methylation changes and the transcriptional responses in the selected apple bud types. We observed that in the apple genome, approximately 79.5%, 67.4% and 23.7% of the CG, CHG and CHH sequences are methylated, respectively. For each sequence context, differentially methylated regions exhibited distinct methylation patterns among the analyzed apple bud types. Global methylation and transcriptional analyses revealed that nonexpressed genes or genes expressed at low levels were highly methylated in the gene-body regions, suggesting that gene-body methylation is negatively correlated with gene expression. Moreover, genes with methylated promoters were more highly expressed than genes with unmethylated promoters, implying promoter methylation and gene expression are positively correlated. Additionally, flowering-related genes (e.g. SOC1, AP1 and SPLs) and some transcription factor genes (e.g. GATA, bHLH, bZIP and WOX) were highly expressed in spur buds (highest flowering rate), but were associated with low methylation levels in the gene-body regions. Our findings indicate a potential correlation between DNA methylation and gene expression in apple buds with diverse flowering capabilities, suggesting an epigenetic regulatory mechanism influences apple flower bud formation.


Assuntos
Flores/fisiologia , Malus/genética , Malus/fisiologia , Proteínas de Plantas/metabolismo , Análise de Sequência de RNA/métodos , Metilação de DNA/genética , Metilação de DNA/fisiologia , Flores/genética , Regulação da Expressão Gênica de Plantas/genética , Regulação da Expressão Gênica de Plantas/fisiologia , Proteínas de Plantas/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
13.
Nord J Psychiatry ; 73(4-5): 257-263, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31070508

RESUMO

Background: Prenatal maternal stress increases the risk of offspring developmental and psychological difficulties. The biological mechanisms behind these associations are mostly unknown. One explanation suggests that exposure of the fetus to maternal stress may influence DNA methylation. However, this hypothesis is largely based on animal studies, and human studies of candidate genes from single timepoints. Aim: The aim of this study was to investigate if prenatal maternal stress, in the form of maternal depressive symptoms, was associated with variation in genome-wide DNA methylation at two timepoints. Methods: One-hundred and eighty-four mother-child dyads were selected from a population of pregnant women in the Little-in-Norway study. The Edinburgh Postnatal Depression Scale (EPDS) measured maternal depressive symptoms. It was completed by the pregnant mothers between weeks 17 and 32 of gestation. DNA was obtained from infant saliva cells at two timepoints (age 6 weeks and 12 months). DNA methylation was measured in 274 samples from 6 weeks (n = 146) and 12 months (n = 128) using the Illumina Infinium HumanMethylation 450 BeadChip. Linear regression analyses of prenatal maternal depressive symptoms and infant methylation were performed at 6 weeks and 12 months separately, and for both timepoints together using a mixed model. Results: The analyses revealed no significant genome-wide association between maternal depressive symptoms and infant DNA methylation in the separate analyses and for both timepoints together. Conclusions: This sample of pregnant women and their infants living in Norway did not reveal associations between maternal depressive symptoms and infant DNA methylation.


Assuntos
Metilação de DNA/fisiologia , Depressão/psicologia , Epigenômica/métodos , Complicações na Gravidez/psicologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Adulto , Animais , Depressão/epidemiologia , Depressão/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Recém-Nascido , Estudos Longitudinais , Mães/psicologia , Noruega/epidemiologia , Gravidez , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/genética , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Adulto Jovem
14.
Nat Commun ; 10(1): 2063, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31048693

RESUMO

RELATIVE OF EARLY FLOWERING 6 (REF6/JMJ12), a Jumonji C (JmjC)-domain-containing H3K27me3 histone demethylase, finds its target loci in Arabidopsis genome by directly recognizing the CTCTGYTY motif via its zinc-finger (ZnF) domains. REF6 tends to bind motifs located in active chromatin states that are depleted for heterochromatic modifications. However, the underlying mechanism remains unknown. Here, we show that REF6 preferentially bind to hypo-methylated CTCTGYTY motifs in vivo, and that CHG methylation decreases REF6 DNA binding affinity in vitro. In addition, crystal structures of ZnF-clusters in complex with DNA oligonucleotides reveal that 5-methylcytosine is unfavorable for REF6 binding. In drm1 drm2 cmt2 cmt3 (ddcc) quadruple mutants, in which non-CG methylation is significantly reduced, REF6 can ectopically bind a small number of new target loci, most of which are located in or neighbored with short TEs in euchromatic regions. Collectively, our findings reveal that DNA methylation, likely acting in combination with other epigenetic modifications, may partially explain why REF6 binding is depleted in heterochromatic loci.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/fisiologia , Metilação de DNA/fisiologia , Histonas/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Fatores de Transcrição/metabolismo , 5-Metilcitosina/metabolismo , Epigênese Genética/fisiologia , Eucromatina/metabolismo , Heterocromatina/metabolismo , Mutação , Plantas Geneticamente Modificadas , Dedos de Zinco/fisiologia
15.
Biol Res ; 52(1): 21, 2019 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-30954083

RESUMO

BACKGROUND: Defects in DNA methylation have been shown to be associated with metabolic diseases such as obesity, dyslipidemia, and hypercholesterolemia. To analyze the methylation profile of the ADRB3 gene and correlate it with lipid profile, lipid intake, and oxidative stress based on malondialdehyde (MDA) and total antioxidant capacity (TAC), homocysteine and folic acid levels, nutritional status, lifestyle, and socioeconomic variables in an adult population. A cross-sectional epidemiological study representative of the East and West regions of the municipality of João Pessoa, Paraíba state, Brazil, enrolled 265 adults of both genders. Demographic, lifestyle, and socioeconomic questionnaires and a 24-h recall questionnaire were applied by trained interviewers' home. Nutritional and biochemical evaluation (DNA methylation, lipid profile, MDA, TAC, homocysteine and folic acid levels) was performed. RESULTS: DNA hypermethylation of the ADRB3 gene, analyzed in leukocytes, was present in 50% of subjects and was associated with a higher risk of being overweight (OR 3.28; p = 0.008) or obese (OR 3.06; p = 0.017), a higher waist-hip ratio in males (OR 1.17; p = 0.000), greater intake of trans fats (OR 1.94; p = 0.032), higher LDL (OR 2.64; p = 0.003) and triglycerides (OR 1.81; p = 0.031), and higher folic acid levels (OR 1.85; p = 0.022). CONCLUSIONS: These results suggest that epigenetic changes in the ADRB3 gene locus may explain the development of obesity and non-communicable diseases associated with trans-fat intake, altered lipid profile, and elevated folic acid. Because of its persistence, DNA methylation may have an impact in adults, in association with the development of non-communicable diseases. This study is the first population-based study of the ADRB3 gene, and the data further support evaluation of ADRB3 DNA methylation as an effective biomarker.


Assuntos
Metilação de DNA/fisiologia , Lipídeos/sangue , Obesidade/genética , Receptores Adrenérgicos beta 3/genética , Adulto , Estudos Transversais , Ingestão de Energia , Comportamento Alimentar , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Obesidade/sangue , Obesidade/metabolismo , Fatores Socioeconômicos , Adulto Jovem
16.
Nat Commun ; 10(1): 1679, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30976011

RESUMO

The Polycomb repressive complexes PRC1 and PRC2 act non-redundantly at target genes to maintain transcriptional programs and ensure cellular identity. PRC2 methylates lysine 27 on histone H3 (H3K27me), while PRC1 mono-ubiquitinates histone H2A at lysine 119 (H2Aub1). Here we present engineered mouse embryonic stem cells (ESCs) targeting the PRC2 subunits EZH1 and EZH2 to discriminate between contributions of distinct H3K27 methylation states and the presence of PRC2/1 at chromatin. We generate catalytically inactive EZH2 mutant ESCs, demonstrating that H3K27 methylation, but not recruitment to the chromatin, is essential for proper ESC differentiation. We further show that EZH1 activity is sufficient to maintain repression of Polycomb targets by depositing H3K27me2/3 and preserving PRC1 recruitment. This occurs in the presence of altered H3K27me1 deposition at actively transcribed genes and by a diffused hyperacetylation of chromatin that compromises ESC developmental potential. Overall, this work provides insights for the contribution of diffuse chromatin invasion by acetyltransferases in PRC2-dependent loss of developmental control.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Histonas/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Acetilação , Animais , Diferenciação Celular/fisiologia , Cromatina/metabolismo , Metilação de DNA/fisiologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Técnicas de Inativação de Genes , Camundongos , Células-Tronco Embrionárias Murinas , Complexo Repressor Polycomb 1/metabolismo , Complexo Repressor Polycomb 2/genética
17.
Nat Commun ; 10(1): 1884, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015495

RESUMO

DNA methyltransferases (DNMTs) deposit DNA methylation, which regulates gene expression and is essential for mammalian development. Histone post-translational modifications modulate the recruitment and activity of DNMTs. The PWWP domains of DNMT3A and DNMT3B are posited to interact with histone 3 lysine 36 trimethylation (H3K36me3); however, the functionality of this interaction for DNMT3A remains untested in vivo. Here we present a mouse model carrying a D329A point mutation in the DNMT3A PWWP domain. The mutation causes dominant postnatal growth retardation. At the molecular level, it results in progressive DNA hypermethylation across domains marked by H3K27me3 and bivalent chromatin, and de-repression of developmental regulatory genes in adult hypothalamus. Evaluation of non-CpG methylation, a marker of de novo methylation, further demonstrates the altered recruitment and activity of DNMT3AD329A at bivalent domains. This work provides key molecular insights into the function of the DNMT3A-PWWP domain and role of DNMT3A in regulating postnatal growth.


Assuntos
Cromatina/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Transtornos do Crescimento/genética , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Mutação com Ganho de Função/fisiologia , Transtornos do Crescimento/patologia , Histonas/metabolismo , Humanos , Hipotálamo/metabolismo , Hipotálamo/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação Puntual/fisiologia , Ligação Proteica/genética , Domínios Proteicos/genética , Processamento de Proteína Pós-Traducional/fisiologia
18.
Nat Commun ; 10(1): 1613, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30962443

RESUMO

To properly regulate the genome, cytosine methylation is established by animal DNA methyltransferase 3 s (DNMT3s). While altered DNMT3 homologs, Domains rearranged methyltransferases (DRMs), have been shown to establish methylation via the RNA directed DNA methylation (RdDM) pathway, the role of true-plant DNMT3 orthologs remains elusive. Here, we profile de novo (RPS transgene) and genomic methylation in the basal plant, Physcomitrella patens, mutated in each of its PpDNMTs. We show that PpDNMT3b mediates CG and CHH de novo methylation, independently of PpDRMs. Complementary de novo CHG methylation is specifically mediated by the CHROMOMETHYLASE, PpCMT. Intragenomically, PpDNMT3b functions preferentially within heterochromatin and is affected by PpCMT. In comparison, PpDRMs target active-euchromatic transposons. Overall, our data resolve how DNA methylation in plants can be established in heterochromatin independently of RdDM; suggest that DRMs have emerged to target euchromatin; and link DNMT3 loss in angiosperms to the initiation of heterochromatic CHH methylation by CMT2.


Assuntos
Bryopsida/fisiologia , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/fisiologia , Heterocromatina/genética , Proteínas de Plantas/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , Evolução Molecular , Redes e Vias Metabólicas/fisiologia , Proteínas de Plantas/genética , Plantas Geneticamente Modificadas , Seleção Genética/fisiologia
19.
J Anim Physiol Anim Nutr (Berl) ; 103(3): 858-867, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30900324

RESUMO

DNA methylation is an important epigenetic strategy for embryo development and survival. The one-carbon metabolism can be disturbed by inadequate provision of dietary methyl donors. Because of the continuous selection for larger litters, it is relevant to explore if highly prolific sows might encounter periods of methyl donor deficiency throughout their reproductive cycles. This study, therefore, assesses the fluctuation(s) in methylation potential (MP) and aims to link possible methyl donor deficiencies to nutrient metabolism. In total, 15 hybrid sows were followed from weaning of the previous reproductive cycle (d-5) to weaning of the present cycle. Blood samples were taken at d-5, 0, 21, 42, 63, 84 and d108 of gestation, the day of parturition (d115), two weeks of lactation (d129) and at weaning (d143). Blood plasma samples were analysed for S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), free methionine, free glycine, acetylcarnitine and 3-hydroxybutyrylcarnitine. Serum samples were analysed for urea and creatinine. Generally, MP (i.e. ratio SAM:SAH) increased throughout gestation (p = 0.009), but strongly fluctuated in the period around parturition and weaning. From d108 to parturition, absolute plasma levels of SAM (p < 0.001), SAH (p = 0.031) and methionine (p = 0.001) increased. The first two weeks of lactation were characterised by an increase in MP (p = 0.039) due to a remaining high value of SAM and a distinct decrease in SAH (p = 0.008). During the last two weeks of lactation, MP decreased (p = 0.038) due to a decrease in SAM (p < 0.001) and a stable value for SAH. The methylation reactions seem to continue after weaning, a period crucial for the follicular and embryonic development of the subsequent litter. This study thus demonstrates that the methylation status fluctuates substantially throughout a sow's reproductive cycle, and further research is needed to identify the factors affecting methylation status.


Assuntos
Ração Animal/análise , Metilação de DNA/fisiologia , Dieta/veterinária , Nutrientes/metabolismo , Suínos/fisiologia , Fenômenos Fisiológicos da Nutrição Animal , Animais , Composição Corporal , Peso Corporal , Feminino , Nutrientes/sangue , Gravidez , Suínos/sangue , Suínos/embriologia
20.
Int J Mol Sci ; 20(5)2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30871110

RESUMO

We first demonstrated that long-term increased polyamine (spermine, spermidine, putrescine) intake elevated blood spermine levels in mice and humans, and lifelong consumption of polyamine-rich chow inhibited aging-associated increase in aberrant DNA methylation, inhibited aging-associated pathological changes, and extend lifespan of mouse. Because gene methylation status is closely associated with aging-associated conditions and polyamine metabolism is closely associated with regulation of gene methylation, we investigated the effects of extracellular spermine supplementation on substrate concentrations and enzyme activities involved in gene methylation. Jurkat cells and human mammary epithelial cells were cultured with spermine and/or D,L-alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase. Spermine supplementation inhibited enzymatic activities of adenosylmethionine decarboxylase in both cells. The ratio of decarboxylated S-adenosylmethionine to S-adenosyl-L-methionine increased by DFMO and decreased by spermine. In Jurkat cells cultured with DFMO, the protein levels of DNA methyltransferases (DNMTs) 1, 3A and 3B were not changed, however the activity of the three enzymes markedly decreased. The protein levels of these enzymes were not changed by addition of spermine, DNMT 3A and especially 3B were activated. We show that changes in polyamine metabolism dramatically affect substrate concentrations and activities of enzymes involved in gene methylation.


Assuntos
DNA (Citosina-5-)-Metiltransferases/metabolismo , Espermina/metabolismo , Adenosilmetionina Descarboxilase/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Metilação de DNA/fisiologia , Metilases de Modificação do DNA/metabolismo , Eflornitina/metabolismo , Células Epiteliais/metabolismo , Humanos , Células Jurkat , Glândulas Mamárias Humanas/metabolismo , Ornitina Descarboxilase/metabolismo , Poliaminas/metabolismo , Putrescina/metabolismo , S-Adenosilmetionina/análogos & derivados , S-Adenosilmetionina/metabolismo , Espermidina/metabolismo
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