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1.
Semin Cell Dev Biol ; 97: 172-180, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31587964

RESUMO

The literature about Developmental Origins of Health and Disease (DOHaD) studies is considerably growing. Maternal and paternal environment, during all the development of the individual from gametogenesis to weaning and beyond, as well as the psychosocial environment in childhood and teenage, can shape the adult and the elderly person's susceptibility to her/his own environment and diseases. This non-conventional, non-genetic, inheritance is underlain by several mechanisms among which epigenetics is obviously central, due to the notion of memory of early decisional events during development even when this stimulus is gone, that is implied in Waddington's developmental concept. This review first summarizes the different mechanisms by which the environment can model the epigenome: receptor signalling, energy metabolism and signal mechanotransduction from extracellular matrix to chromatin. Then an overview of the epigenetic changes in response to maternal environment during the vulnerability time windows, gametogenesis, early development, placentation and foetal growth, and postnatal period, is described, with the specific example of overnutrition and food deprivation. The implication of epigenetics in DOHaD is obvious, however the precise causal chain from early environment to the epigenome modifications to the phenotype still needs to be deciphered.


Assuntos
Doença/genética , Epigenoma/genética , Epigenômica/métodos , Predisposição Genética para Doença , Humanos , Pais , Fenótipo , Transdução de Sinais
2.
Mol Reprod Dev ; 87(1): 124-134, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31746511

RESUMO

Highly differentiated mature spermatozoa carry not only genetic but also epigenetic information that is to be transmitted to the embryo. DNA methylation is one epigenetic actor associated with sperm nucleus compaction, gene silencing, and prepatterning of embryonic gene expression. Therefore, the stability of this mark toward reproductive biotechnologies is a major issue in animal production. The present work explored the impact of hormonal induction of spermiation and sperm cryopreservation in two cyprinids, the goldfish (Carassius auratus) and the zebrafish (Danio rerio), using LUminometric Methylation Assay (LUMA). We showed that while goldfish hormonal treatment did increase sperm production, it did not alter global DNA methylation of spermatozoa. Different sperm samples repeatedly collected from the same males for 2 months also showed the same global DNA methylation level. Similarly, global DNA methylation was not affected after cryopreservation of goldfish spermatozoa with methanol, whereas less efficient cryoprotectants (dimethylsulfoxide and 1,2-propanediol) decreased DNA methylation. In contrast, cryopreservation of zebrafish spermatozoa with methanol induced a slight, but significant, increase in global DNA methylation. In the less compact nuclei, that is, goldfish fin somatic cells, cryopreservation did not change global DNA methylation regardless of the choice of cryoprotectant. To conclude, global DNA methylation is a robust parameter with respect to biotechnologies such as hormonal induction of spermiation and sperm cryopreservation, but it can be altered when the best sperm manipulation conditions are not met.


Assuntos
Criopreservação/métodos , Metilação de DNA/efeitos dos fármacos , Domperidona/farmacologia , Carpa Dourada/genética , Hormônio Liberador de Gonadotropina/farmacologia , Preservação do Sêmen/métodos , Espermatozoides , Peixe-Zebra/genética , Animais , Crioprotetores/farmacologia , Dimetil Sulfóxido/farmacologia , Combinação de Medicamentos , Feminino , Fertilização in vitro/métodos , Masculino , Metanol/farmacologia , Oócitos , Propilenoglicol/farmacologia , Motilidade dos Espermatozoides/efeitos dos fármacos
3.
Development ; 143(6): 962-71, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26980793

RESUMO

The H19 locus controls fetal growth by regulating expression of several genes from the imprinted gene network (IGN). H19 is fully repressed after birth, except in skeletal muscle. Using loss-of-function H19(Δ3) mice, we investigated the function of H19 in adult muscle. Mutant muscles display hypertrophy and hyperplasia, with increased Igf2 and decreased myostatin (Mstn) expression. Many imprinted genes are expressed in muscle stem cells or satellite cells. Unexpectedly, the number of satellite cells was reduced by 50% in H19(Δ3) muscle fibers. This reduction occurred after postnatal day 21, suggesting a link with their entry into quiescence. We investigated the biological function of these mutant satellite cells in vivo using a regeneration assay induced by multiple injections of cardiotoxin. Surprisingly, despite their reduced number, the self-renewal capacity of these cells is fully retained in the absence of H19. In addition, we observed a better regeneration potential of the mutant muscles, with enhanced expression of several IGN genes and genes from the IGF pathway.


Assuntos
Redes Reguladoras de Genes , Impressão Genômica , Músculos/fisiologia , RNA Longo não Codificante/metabolismo , Regeneração/genética , Animais , Cardiotoxinas/toxicidade , Contagem de Células , Proliferação de Células/efeitos dos fármacos , Deleção de Genes , Redes Reguladoras de Genes/efeitos dos fármacos , Impressão Genômica/efeitos dos fármacos , Hiperplasia , Hipertrofia , Masculino , Camundongos Endogâmicos C57BL , Músculos/efeitos dos fármacos , Músculos/patologia , Mioblastos/efeitos dos fármacos , Mioblastos/patologia , RNA Longo não Codificante/genética , Regeneração/efeitos dos fármacos , Células Satélites de Músculo Esquelético/patologia
4.
FASEB J ; 32(5): 2768-2778, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29295860

RESUMO

According to the Developmental Origin of Health and Disease (DOHaD) concept, maternal obesity and accelerated growth in neonates program obesity later in life. White adipose tissue (WAT) has been the focus of developmental programming events, although underlying mechanisms remain elusive. In rodents, WAT development primarily occurs during lactation. We previously reported that adult rat offspring from dams fed a high-fat (HF) diet exhibited fat accumulation and decreased peroxisome proliferator-activated receptor γ (PPARγ) mRNA levels in WAT. We hypothesized that PPARγ down-regulation occurs via epigenetic malprogramming which takes place during adipogenesis. We therefore examined epigenetic modifications in the PPARγ1 and PPARγ2 promoters in perirenal (pWAT) and inguinal fat pads of HF offspring at weaning (postnatal d 21) and in adulthood. Postnatal d 21 is a period characterized by active epigenomic remodeling in the PPARγ2 promoter (DNA hypermethylation and depletion in active histone modification H3ac and H3K4me3) in pWAT, consistent with increased DNA methyltransferase and DNA methylation activities. Adult HF offspring exhibited sustained hypermethylation and histone modification H3ac of the PPARγ2 promoter in both deposits, correlated with persistent decreased PPARγ2 mRNA levels. Consistent with the DOHaD hypothesis, retained epigenetic marks provide a mechanistic basis for the cellular memory linking maternal obesity to a predisposition for later adiposity.-Lecoutre, S., Pourpe, C., Butruille, L., Marousez, L., Laborie, C., Guinez, C., Lesage, J., Vieau, D., Eeckhoute, J., Gabory, A., Oger, F., Eberlé, D., Breton, C. Reduced PPARγ2 expression in adipose tissue of male rat offspring from obese dams is associated with epigenetic modifications.


Assuntos
Tecido Adiposo/metabolismo , Metilação de DNA , Epigênese Genética , Obesidade/metabolismo , PPAR gama/biossíntese , Regiões Promotoras Genéticas , Tecido Adiposo/patologia , Adiposidade/genética , Animais , Feminino , Histonas/genética , Histonas/metabolismo , Masculino , Obesidade/genética , PPAR gama/genética , Processamento de Proteína Pós-Traducional , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Wistar
5.
J Exp Biol ; 218(Pt 1): 50-8, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25568451

RESUMO

The recent and rapid worldwide increase in non-communicable diseases challenges the assumption that genetic factors are the primary contributors to such diseases. A new concept of the 'developmental origins of health and disease' (DOHaD) is at stake and therefore requires a paradigm shift. Maternal obesity and malnutrition predispose offspring to develop metabolic syndrome, a vicious cycle leading to transmission to subsequent generation(s), with differences in response and susceptibility according to the sex of the individual. The placenta is a programming agent of adult health and disease. Adaptations of placental phenotype in response to maternal diet and metabolic status alter fetal nutrient supply. This implies important epigenetic changes that are, however, still poorly documented in DOHaD studies, particularly concerning overnutrition. The aim of this review is to discuss the emerging knowledge on the relationships between the effect of maternal nutrition or metabolic status on placental function and the risk of diseases later in life, with a specific focus on epigenetic mechanisms and sexual dimorphism. Explaining the sex-specific causal variables and how males versus females respond and adapt to environmental perturbations should help physicians and patients to anticipate disease susceptibility.


Assuntos
Doença/genética , Epigênese Genética , Saúde , Fenômenos Fisiológicos da Nutrição Materna , Placenta/metabolismo , Animais , Feminino , Gravidez , Caracteres Sexuais
6.
Am J Physiol Endocrinol Metab ; 304(1): E14-22, 2013 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23092912

RESUMO

Low birth weight is associated with an increased risk for developing type 2 diabetes and metabolic diseases. The placental capacity to supply nutrients and oxygen to the fetus represents the main determiner of fetal growth. However, few studies have investigated the effects of maternal diet on the placenta. We explored placental adaptive proteomic processes implicated in response to maternal undernutrition. Rat term placentas from 70% food-restricted (FR30) mothers were used for a proteomic screen. Placental mitochondrial functions were evaluated using molecular and functional approaches, and ATP production was measured. FR30 drastically reduced placental and fetal weights. FR30 placentas displayed 14 proteins that were differentially expressed, including several mitochondrial proteins. FR30 induced a marked increase in placental mtDNA content and changes in mitochondrial functions, including modulation of the expression of genes implicated in biogenesis and bioenergetic pathways. FR30 mitochondria showed higher oxygen consumption but failed to maintain their ATP production. Maternal undernutrition induces placental mitochondrial abnormalities. Although an increase in biogenesis and bioenergetic efficiency was noted, placental ATP level was reduced. Our data suggest that placental mitochondrial defects may be implicated in fetoplacental pathologies.


Assuntos
Restrição Calórica/efeitos adversos , Metabolismo Energético/fisiologia , Retardo do Crescimento Fetal/etiologia , Fenômenos Fisiológicos da Nutrição Materna , Mitocôndrias/fisiologia , Placenta/metabolismo , Animais , Eficiência/fisiologia , Feminino , Retardo do Crescimento Fetal/metabolismo , Masculino , Troca Materno-Fetal/fisiologia , Mitocôndrias/metabolismo , Placenta/fisiologia , Placenta/ultraestrutura , Circulação Placentária/fisiologia , Gravidez , Ratos , Ratos Wistar
7.
Reprod Biol Endocrinol ; 11: 10, 2013 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-23433040

RESUMO

BACKGROUND: Stereology is an established method to extrapolate three-dimensional quantities from two-dimensional images. It was applied to placentation in the mouse, but not yet for other rodents. Herein, we provide the first study on quantitative placental development in a sigmodontine rodent species with relatively similar gestational time. Placental structure was also compared to the mouse, in order to evaluate similarities and differences in developmental patterns at the end of gestation. METHODS: Fetal and placental tissues of Necromys lasiurus were collected and weighed at 3 different stages of gestation (early, mid and late gestation) for placental stereology. The total and relative volumes of placenta and of its main layers were investigated. Volume fractions of labyrinth components were quantified by the One Stop method in 31 placentae collected from different individuals, using the Mercator software. Data generated at the end of gestation from N. lasiurus placentae were compared to those of Mus musculus domesticus obtained at the same stage. RESULTS: A significant increase in the total absolute volumes of the placenta and its main layers occurred from early to mid-gestation, followed by a reduction near term, with the labyrinth layer becoming the most prominent area. Moreover, at the end of gestation, the total volume of the mouse placenta was significantly increased compared to that of N. lasiurus although the proportions of the labyrinth layer and junctional zones were similar. Analysis of the volume fractions of the components in the labyrinth indicated a significant increase in fetal vessels and sinusoidal giant cells, a decrease in labyrinthine trophoblast whereas the proportion of maternal blood space remained stable in the course of gestation. On the other hand, in the mouse, volume fractions of fetal vessels and sinusoidal giant cells decreased whereas the volume fraction of labyrinthine trophoblast increased compared to N. lasiurus placenta. CONCLUSIONS: Placental development differed between N. lasiurus and M. musculus domesticus. In particular, the low placental efficiency in N. lasiurus seemed to induce morphological optimization of fetomaternal exchanges. In conclusion, despite similar structural aspects of placentation in these species, the quantitative dynamics showed important differences.


Assuntos
Camundongos/embriologia , Muridae/embriologia , Placenta/embriologia , Placentação/fisiologia , Sigmodontinae/embriologia , Animais , Arvicolinae/embriologia , Arvicolinae/crescimento & desenvolvimento , Feminino , Camundongos/crescimento & desenvolvimento , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Muridae/crescimento & desenvolvimento , Placenta/citologia , Gravidez , Sigmodontinae/crescimento & desenvolvimento , Especificidade da Espécie
8.
Front Nutr ; 10: 1190392, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37565037

RESUMO

Introduction: In humans, adversity in childhood exerts enduring effects on brain and increases the vulnerability to psychiatric diseases. It also leads to a higher risk of eating disorders and obesity. Maternal separation (MS) in mice has been used as a proxy of stress during infancy. We hypothesized that MS in mice affects motivation to obtain palatable food in adulthood and changes gene expression in reward system. Methods: Male and female pups from C57Bl/6J and C3H/HeN mice strains were subjected to a daily MS protocol from postnatal day (PND) 2 to PND14. At adulthood, their motivation for palatable food reward was assessed in operant cages. Results: Compared to control mice, male and female C3H/HeN mice exposed to MS increased their instrumental response for palatable food, especially when the effort required to obtain the reward was high. Importantly, this effect is shown in animals fed ad libitum. Transcriptional analysis revealed 375 genes differentially expressed in the nucleus accumbens of male MS C3H/HeN mice compared to the control group, some of these being associated with the regulation of the reward system (e.g., Gnas, Pnoc). Interestingly, C57Bl/6J mice exposed to MS did not show alterations in their motivation to obtain a palatable reward, nor significant changes in gene expression in the nucleus accumbens. Conclusion: MS produces long-lasting changes in motivation for palatable food in C3H/HeN mice, but has no impact in C57Bl/6J mice. These behavioral alterations are accompanied by drastic changes in gene expression in the nucleus accumbens, a key structure in the regulation of motivational processes.

9.
Hum Mol Genet ; 19(9): 1779-90, 2010 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-20150233

RESUMO

Genomic imprinting regulates the expression of a group of genes monoallelically expressed in a parent-of-origin specific manner. Allele-specific DNA methylation occurs at differentially methylated regions (DMRs) of these genes. We have previously shown that in vitro fertilization and embryo culture result in methylation defects at the imprinted H19-Igf2 locus at the blastocyst stage. The current study was designed to evaluate the consequences of these manipulations on genomic imprinting after implantation in the mouse. Blastocysts were produced following three experimental conditions: (i) embryos maintained in culture medium after in vivo fertilization or (ii) in vitro fertilization and (iii) a control group with embryos obtained after in vivo fertilization and timed mating. Blastocysts were all transplanted into pseudopregnant females. Embryos and placentas were collected on day 10.5 of development. DNA methylation patterns of the H19, Igf2, Igf2r and Dlk1-Dio3 DMRs were analyzed by quantitative pyrosequencing. In contrast to blastocyst stage, methylation profiles were normal both in embryonic and placental tissues after in vitro fertilization and culture. Expression of a selected set of imprinting genes from the recently described imprinted gene network (IGN) (including Igf2 and H19) was analyzed in placental tissues by quantitative RT-PCR. Placentas obtained after in vitro fertilization and embryo culture displayed significantly disturbed levels of H19 and Igf2 mRNA, as well as of most other genes from the IGN. As embryos were phenotypically normal, we hypothesize that the modulation of a coordinated network of imprinted genes results in a compensatory process capable of correcting potential dysfunction of placenta.


Assuntos
Metilação de DNA/fisiologia , Desenvolvimento Embrionário/fisiologia , Redes Reguladoras de Genes/fisiologia , Impressão Genômica/fisiologia , Placenta/embriologia , Animais , Feminino , Fertilização in vitro , Componentes do Gene , Redes Reguladoras de Genes/genética , Impressão Genômica/genética , Técnicas In Vitro , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Camundongos , Gravidez , RNA Longo não Codificante , RNA não Traduzido/genética , RNA não Traduzido/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
10.
Development ; 136(20): 3413-21, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19762426

RESUMO

The imprinted H19 gene produces a non-coding RNA of unknown function. Mice lacking H19 show an overgrowth phenotype, due to a cis effect of the H19 locus on the adjacent Igf2 gene. To explore the function of the RNA itself, we produced transgenic mice overexpressing H19. We observed postnatal growth reduction in two independent transgenic lines and detected a decrease of Igf2 expression in embryos. An extensive analysis of several other genes from the newly described imprinted gene network (IGN) was performed in both loss- and gain-of-function animals. We found that H19 deletion leads to the upregulation of several genes of the IGN. This overexpression is restored to the wild-type level by transgenic expression of H19. We therefore propose that the H19 gene participates as a trans regulator in the fine-tuning of this IGN in the mouse embryo. This is the first in vivo evidence of a functional role for the H19 RNA. Our results also bring further experimental evidence for the existence of the IGN and open new perspectives in the comprehension of the role of genomic imprinting in embryonic growth and in human imprinting pathologies.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , RNA não Traduzido/genética , Sequências Reguladoras de Ácido Nucleico , Animais , Feminino , Fator de Crescimento Insulin-Like II/genética , Masculino , Camundongos , Camundongos Transgênicos , Fenótipo , RNA Longo não Codificante
11.
Bioessays ; 32(6): 473-80, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20486133

RESUMO

The H19 gene produces a non-coding RNA, which is abundantly expressed during embryonic development and down-regulated after birth. Although this gene was discovered over 20 years ago, its function has remained unclear. Only recently a role was identified for the non-coding RNA and/or its microRNA partner, first as a tumour suppressor gene in mice, then as a trans-regulator of a group of co-expressed genes belonging to the imprinted gene network that is likely to control foetal and early postnatal growth in mice. The mechanisms underlying this transcriptional or post-transcriptional regulation remain to be discovered, perhaps by identifying the protein partners of the full-length H19 RNA or the targets of the microRNA. This first in vivo evidence of a functional role for the H19 locus provides new insights into how genomic imprinting helps to control embryonic growth.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Impressão Genômica/fisiologia , RNA não Traduzido/metabolismo , Animais , Regulação da Expressão Gênica no Desenvolvimento/genética , Impressão Genômica/genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante , RNA não Traduzido/genética
12.
Med Sci (Paris) ; 28(2): 185-92, 2012 Feb.
Artigo em Francês | MEDLINE | ID: mdl-22377307

RESUMO

A new definition of sexual dimorphism is required. The divergent biology of the sexes is still largely ignored, overshadowed by sociocultural considerations and confined to its hormonal organizational and activational effects, while the genes unequally expressed by the sex chromosomes play an important role much earlier, after conception, to set the stage and throughout life. These different components have independent and parallel effects that can interact in a synergistic or antagonistic manner on differentiation and response processes to trigger or erase sex-specific differences. The epigenetic marks and machinery represent the perfect tools to keep the memory of which sex is ours from the very beginning of life. Within the context of the developmental origin of adult health and diseases (DOHaD), owing to their flexibility to the environment, epigenetic marks also represent a support to archive the effects of environments during development, according to the sex of the parent, in a sex-specific mode. In all tissues, including gonads and brain, different trajectories of genes and pathways are used at the basal levels and to modulate/dictate responses according to sex and gender. It is urgent to emphasize the need to take into consideration this new knowledge and to apply less sex-biased approaches in research, medicine and society, to enhance women health and well-being. A critical review and realization of gender-specific social constraints, an indeniably but slowly on-going process, should allow us to "set free our sex biology" while detracting the delusion of hierarchy of the complex mechanisms involved.


Assuntos
Caracteres Sexuais , Diferenciação Sexual/fisiologia , Adulto , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologia , Desenvolvimento Embrionário/genética , Desenvolvimento Embrionário/fisiologia , Epigênese Genética/fisiologia , Feminino , Interação Gene-Ambiente , História do Século XXI , Humanos , Masculino , Modelos Biológicos , Gravidez , Diferenciação Sexual/genética , Fatores Socioeconômicos
13.
Proc Natl Acad Sci U S A ; 105(34): 12417-22, 2008 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-18719115

RESUMO

The H19 locus belongs to a cluster of imprinted genes that is linked to the human Beckwith-Wiedemann syndrome. The expression of H19 and its closely associated IGF2 gene is frequently deregulated in some human tumors, such as Wilms' tumors. In these cases, biallelic IGF2 expression and lack of expression of H19 are associated with hypermethylation of the imprinting center of this locus. These observations and others have suggested a potential tumor suppressor effect of the H19 locus. Some studies have also suggested that H19 is an oncogene, based on tissue culture systems. We show, using in vivo murine models of tumorigenesis, that the H19 locus controls the size of experimental teratocarcinomas, the number of polyps in the Apc murine model of colorectal cancer and the timing of appearance of SV40-induced hepatocarcinomas. The H19 locus thus clearly displays a tumor suppressor effect in mice.


Assuntos
Genes Supressores de Tumor/fisiologia , RNA não Traduzido/fisiologia , Animais , Carcinoma Hepatocelular/patologia , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Fator de Crescimento Insulin-Like II , Camundongos , Camundongos Mutantes , Família Multigênica , RNA Longo não Codificante , RNA não Traduzido/classificação , Teratoma/patologia
14.
J Cachexia Sarcopenia Muscle ; 12(4): 1064-1078, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34196129

RESUMO

BACKGROUND: Knowledge of age-related DNA methylation changes in skeletal muscle is limited, yet this tissue is severely affected by ageing in humans. METHODS: We conducted a large-scale epigenome-wide association study meta-analysis of age in human skeletal muscle from 10 studies (total n = 908 muscle methylomes from men and women aged 18-89 years old). We explored the genomic context of age-related DNA methylation changes in chromatin states, CpG islands, and transcription factor binding sites and performed gene set enrichment analysis. We then integrated the DNA methylation data with known transcriptomic and proteomic age-related changes in skeletal muscle. Finally, we updated our recently developed muscle epigenetic clock (https://bioconductor.org/packages/release/bioc/html/MEAT.html). RESULTS: We identified 6710 differentially methylated regions at a stringent false discovery rate <0.005, spanning 6367 unique genes, many of which related to skeletal muscle structure and development. We found a strong increase in DNA methylation at Polycomb target genes and bivalent chromatin domains and a concomitant decrease in DNA methylation at enhancers. Most differentially methylated genes were not altered at the mRNA or protein level, but they were nonetheless strongly enriched for genes showing age-related differential mRNA and protein expression. After adding a substantial number of samples from five datasets (+371), the updated version of the muscle clock (MEAT 2.0, total n = 1053 samples) performed similarly to the original version of the muscle clock (median of 4.4 vs. 4.6 years in age prediction error), suggesting that the original version of the muscle clock was very accurate. CONCLUSIONS: We provide here the most comprehensive picture of DNA methylation ageing in human skeletal muscle and reveal widespread alterations of genes involved in skeletal muscle structure, development, and differentiation. We have made our results available as an open-access, user-friendly, web-based tool called MetaMeth (https://sarah-voisin.shinyapps.io/MetaMeth/).


Assuntos
Metilação de DNA , Proteômica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ilhas de CpG , Epigênese Genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético , Adulto Jovem
15.
Curr Opin Clin Nutr Metab Care ; 13(3): 284-93, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20375884

RESUMO

PURPOSE OF REVIEW: The ways in which epigenetic modifications fix the effects of early environmental events, ensuring sustained responses to transient stimuli, which result into modified gene expression patterns and phenotypes later in life, is a topic of considerable interest. This review focuses on recently discovered mechanisms and calls into question prevailing views about the dynamics, positions and functions of relevant epigenetic marks. RECENT FINDINGS: Animal models, including mice, rats, sheep, pigs and rabbits, remain a vital tool for studying the influence of early nutritional events on adult health and disease. Most epigenetic studies have addressed the long-term effects on a small number of epigenetic marks, at the global or individual gene level, of environmental stressors in humans and animal models. They have demonstrated the existence of a self-propagating epigenetic cycle. In parallel, an increasing number of studies based on high-throughput technologies and focusing on humans and mice have revealed additional complexity in epigenetic processes, by highlighting the importance of crosstalk between the different epigenetic marks. In recent months, a number of studies focusing on the developmental origin of health and disease and metabolic programming have identified links between early nutrition, epigenetic processes and long-term illness. SUMMARY: Despite recent progress, we are still far from understanding how, when and where environmental stressors disturb key epigenetic mechanisms. Thus, identifying the original key marks and their changes throughout development, during an individual's lifetime or over several generations, remains a challenging issue.


Assuntos
Epigênese Genética , Desenvolvimento Fetal/genética , Regulação da Expressão Gênica no Desenvolvimento , Expressão Gênica , Fenômenos Fisiológicos da Nutrição do Lactente/genética , Fenômenos Fisiológicos da Nutrição Pré-Natal/genética , Adulto , Animais , Metilação de DNA , Feminino , Predisposição Genética para Doença , Histonas , Humanos , Lactente , Fenótipo , Gravidez
16.
Nutrients ; 12(6)2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32481497

RESUMO

Nutritional changes during developmental windows are of particular concern in offspring metabolic disease. Questions are emerging concerning the role of maternal weight changes before conception, particularly for weight loss, in the development of diet-related disorders. Understanding the physiological pathways affected by the maternal trajectories in the offspring is therefore essential, but a broad overview is still lacking. We recently reported both metabolic and behavioral negative outcomes in offspring born to obese or weight-loss mothers and fed a control of high-fat diet, suggesting long-term modeling of metabolic pathways needing to be further characterized. Using non-targeted LC-HRMS, we investigated the impact of maternal and post-weaning metabolic status on the adult male offspring's metabolome in three tissues involved in energy homeostasis: liver, hypothalamus and olfactory bulb. We showed that post-weaning diet interfered with the abundance of several metabolites, including 1,5-anhydroglucitol, saccharopine and ßhydroxybutyrate, differential in the three tissues. Moreover, maternal diet had a unique impact on the abundance of two metabolites in the liver. Particularly, anserine abundance, lowered by maternal obesity, was normalized by a preconceptional weight loss, whatever the post-weaning diet. This study is the first to identify a programming long-term effect of maternal preconception obesity on the offspring metabolome.


Assuntos
Encéfalo/metabolismo , Dieta , Fígado/metabolismo , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Troca Materno-Fetal/fisiologia , Metaboloma , Obesidade Materna/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Desmame , Ácido 3-Hidroxibutírico/metabolismo , Animais , Anserina/metabolismo , Desoxiglucose/metabolismo , Metabolismo Energético , Feminino , Homeostase , Lisina/análogos & derivados , Lisina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Gravidez
17.
Nutrients ; 11(5)2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31035463

RESUMO

According to the "developmental origins of health and disease" (DOHaD) concept, maternal obesity predisposes the offspring to non-communicable diseases in adulthood. While a preconceptional weight loss (WL) is recommended for obese women, its benefits on the offspring have been poorly addressed. We evaluated whether preconceptional WL was able to reverse the adverse effects of maternal obesity in a mouse model, exhibiting a modification of foetal growth and of the expression of genes encoding epigenetic modifiers in liver and placenta. We tracked metabolic and olfactory behavioural trajectories of offspring born to control, obese or WL mothers. After weaning, the offspring were either put on a control diet (CD) or a high-fat (HFD). After only few weeks of HFD, the offspring developed obesity, metabolic alterations and olfactory impairments, independently of maternal context. However, male offspring born to obese mother gained even more weight under HFD than their counterparts born to lean mothers. Preconceptional WL normalized the offspring metabolic phenotypes but had unexpected effects on olfactory performance: a reduction in olfactory sensitivity, along with a lack of fasting-induced, olfactory-based motivation. Our results confirm the benefits of maternal preconceptional WL for male offspring metabolic health but highlight some possible adverse outcomes on olfactory-based behaviours.


Assuntos
Metabolismo Energético/fisiologia , Obesidade/metabolismo , Olfato/fisiologia , Redução de Peso , Animais , Dieta Hiperlipídica/efeitos adversos , Feminino , Fertilização , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mães , Gravidez
18.
Mol Metab ; 6(8): 922-930, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28752055

RESUMO

OBJECTIVE: According to the Developmental Origin of Health and Disease (DOHaD) concept, maternal obesity and accelerated growth in neonates predispose offspring to white adipose tissue (WAT) accumulation. In rodents, adipogenesis mainly develops during lactation. The mechanisms underlying the phenomenon known as developmental programming remain elusive. We previously reported that adult rat offspring from high-fat diet-fed dams (called HF) exhibited hypertrophic adipocyte, hyperleptinemia and increased leptin mRNA levels in a depot-specific manner. We hypothesized that leptin upregulation occurs via epigenetic malprogramming, which takes place early during development of WAT. METHODS: As a first step, we identified in silico two potential enhancers located upstream and downstream of the leptin transcription start site that exhibit strong dynamic epigenomic remodeling during adipocyte differentiation. We then focused on epigenetic modifications (methylation, hydroxymethylation, and histone modifications) of the promoter and the two potential enhancers regulating leptin gene expression in perirenal (pWAT) and inguinal (iWAT) fat pads of HF offspring during lactation (postnatal days 12 (PND12) and 21 (PND21)) and in adulthood. RESULTS: PND12 is an active period for epigenomic remodeling in both deposits especially in the upstream enhancer, consistent with leptin gene induction during adipogenesis. Unlike iWAT, some of these epigenetic marks were still observable in pWAT of weaned HF offspring. Retained marks were only visible in pWAT of 9-month-old HF rats that showed a persistent "expandable" phenotype. CONCLUSIONS: Consistent with the DOHaD hypothesis, persistent epigenetic remodeling occurs at regulatory regions especially within intergenic sequences, linked to higher leptin gene expression in adult HF offspring in a depot-specific manner.


Assuntos
Epigênese Genética , Leptina/genética , Obesidade/genética , Complicações na Gravidez/genética , Tecido Adiposo Branco/metabolismo , Animais , Metilação de DNA , Feminino , Código das Histonas , Leptina/metabolismo , Masculino , Gravidez , Ratos , Ratos Wistar , Regulação para Cima
19.
Med Sci (Paris) ; 32(1): 66-73, 2016 Jan.
Artigo em Francês | MEDLINE | ID: mdl-26850609

RESUMO

Located at the feto-maternal interface, the placenta is involved in exchange, endocrine and immune functions, which impact fetal development. In contact with the maternal environment, this organ is sensitive to metabolic disorders as over-nutrition, obesity or diabetes. The alteration of blood parameters associated with these pathologies affects placental histology, vascularization and nutrient transfers and, according to the types of troubles, induces local inflammation or hypoxia. These placental changes lead to disturbance of development and fetal growth, which increase the risk of pathologies in offspring in adulthood. The placenta thus appears as a crucial player in the fetal programming.


Assuntos
Diabetes Mellitus/fisiopatologia , Obesidade/fisiopatologia , Placenta/fisiologia , Complicações na Gravidez/fisiopatologia , Feminino , Desenvolvimento Fetal/fisiologia , Humanos , Troca Materno-Fetal/fisiologia , Gravidez , Gravidez em Diabéticas/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia
20.
Med Sci (Paris) ; 32(1): 93-9, 2016 Jan.
Artigo em Francês | MEDLINE | ID: mdl-26850613

RESUMO

The human newborn is highly dependent on parental care for its survival but also for the healthy development of its brain. A large body of literature demonstrates the impact of early life adversity, even during the prenatal period, on the adult's health. The susceptibility to neuropsychiatric diseases is often potentiated by early stress. If there is an agreement that a critical developmental period exists, the mechanisms underlying the long term effects of early life adversity are still poorly understood. Recent studies in animals highlight the involvement of epigenetic processes in the transmission of such vulnerabilities, notably via modifications in germ cells, which can be transmitted in the next generations.


Assuntos
Suscetibilidade a Doenças , Transtornos Mentais/etiologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Estresse Psicológico/complicações , Adulto , Animais , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Modelos Animais de Doenças , Suscetibilidade a Doenças/psicologia , Epigênese Genética , Feminino , Humanos , Recém-Nascido , Transtornos Mentais/epidemiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Estresse Psicológico/epidemiologia
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