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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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Benoit, Henry, Fneich, Mathou, Xia, Foury, Jouin, Junien, Capuron, Jouneau, Moisan, Delpierre, Gabory and Darnaudéry.)

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/)., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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., (© 2016 médecine/sciences – Inserm.)

According to the new paradigm of the Developpemental Origins of Health and Disease (DOHaD), the environmental factors to which an individual is exposed throughout his life can leave an epigenetic footprint on the genome. A crucial period is the early development, where the epigenome is particularly sensitive to the effects of the environment, and during which the individual builds up his health capital that will enable him to respond more or less well to the vagaries of life. The research challenge is to decipher the modes of action and the epigenetic mechanisms put into play by environmental factors that lead to increased disease susceptibility or resilience. The challenge for health is to translate these scientific discoveries into action through, among others, the establishment of preventive recommendations to slow down the growing incidence of non communicable diseases., (© 2016 médecine/sciences – Inserm.)

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., (© 2016 médecine/sciences – Inserm.)

The existence of non-genetic and non-cultural mechanisms that transfer information on the memory of parental exposures to various environments, determining the reactivity of the following generations to their environments during their life, are of growing interest. Yet fundamental questions remain about the nature, the roles and relative importance of epigenetic marks and processes, non-coding RNAs, or other mechanisms, and their persistence over generations. A model incorporating the various transmission systems, their cross-talks and windows of susceptibility to the environment as a function of sex/gender of parent and offspring, has yet to be built., (© 2016 médecine/sciences – Inserm.)

The environment, defined broadly by all that is external to the individual, conditions the phenotype during development, particularly the susceptibility to develop non-communicable diseases. This notion, called Developmental Origins of Health and Disease (DOHaD), is based on numerous epidemiological studies as well as animal models. Thus, parental nutrition and obesity can predispose the offspring to develop metabolic and cardiovascular diseases in adulthood. The known underlying mechanisms include an altered development of tissues that adapt to maternal metabolic condition, and a placental dysfunction, which in turn impacts fetal growth and development. Epigenetic mechanisms modulate gene expression without affecting the DNA sequence itself. The main epigenetic marks are DNA methylation and histone post-translational modifications. These marks are erased and set-up during gametogenesis and development in order to ensure cellular identity. Therefore, they can lead to a memorisation of early environment and induce long-term alteration of cell and tissue functions, which will condition the susceptibility to non-communicable diseases. The placenta is a programming agent of adult disease. The environment, such as smoking or psychosocial stress, is able to modify epigenetic processes in placenta, such as small RNA expression and DNA methylation. We showed that placenta is sensitive to maternal obesity and maternal nutrition, in terms of histology, transcription and epigenetic marks. A clear sexual dimorphism is remarkable in the placental response to maternal environment. In adulthood, the phenotype is also different between males and females. Epigenetic mechanisms could underlie this differential response of males and females to the same environment. The DOHaD can no longer be ignored in Biology of Reproduction. The prevention of non-communicable diseases must take this new paradigm into account. Research will allow a better comprehension of the mechanisms of this early conditioning and the marked sexual dimorphism it is associated to., (© Société de Biologie, 2015.)

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., (© 2012 médecine/sciences – Inserm / SRMS.)

Genomic imprinting leads to parent-of-origin-specific monoallelic expression of about 60 known genes in the mammalian genome. It was discovered 20 years ago and the aim of this review is to summarize its main characteristics. The nature of the imprint, still unknown, is characterized by differential chromatin structure and DNA methylation. The imprint is reset at each generation during gametogenesis, which can be observed by demethylation in the PGCs, then gamete-specific remethylation. The imprinted genes are usually located in clusters and regulated by cis sequences such as imprinting centres, trans factors such as the insulator protein CTCF and/or large non coding antisense RNAs. Genetic and epigenetic abnormalities of the imprinted clusters can lead to human diseases such as Prader-Willi, Angelman or Beckwith-Wiedemann syndromes.