Claudine Junien

Developmental programming and epigenetics

The ways in which epigenetic modifications fix the effects of early environmental events, ensuring sustained responses to transient stimuli that result in modified gene expression patterns and phenotypes later in life, are a topic of considerable interest. This article focuses on recently discovered mechanisms and calls into question prevailing views about the dynamics, positions, and functions of epigenetic marks. Most epigenetic studies have addressed the long-term effects of environmental stressors on a small number of epigenetic marks, at the global or individual gene level, in humans and in animal models. In parallel, increasing numbers of studies based on high-throughput technologies are revealing additional complexity in epigenetic processes by highlighting the importance of crosstalk between different epigenetic marks in humans and mice. A number of studies focusing on metabolic programming and the developmental origin of health and disease have identified links between early nutrition, epigenetic processes, and long-term illness. The existence of a self-propagating epigenetic cycle has been shown. Moreover, recent studies have shown an obvious sexual dimorphism both for programming trajectories and in response to the same environmental insult. Despite recent progress, however, we are still far from understanding how, when, and where environmental stressors disturb key epigenetic mechanisms. Thus, the need to identify original key marks and monitor the changes they undergo throughout development, during an individuals lifetime, or over several generations remains a challenging issue.

Maternal environment and the reproductive function of the offspring

Fetal programming of metabolic diseases is now a well established concept. The scope of the Developmental Origins of Health and Disease has, however, widened and led to the identification of new targets of fetal programming, notably effects on reproductive function. Epidemiologic studies about maternal nutrition and effects on offsprings fertility are rare, but a link between impaired fetal growth, possibly caused by maternal malnutrition, and reproductive function, has been established. The methodologic limitations inherent to human epidemiologic studies can be complemented through the use of animal models, which enable experimental studies on maternal environment and its effect on reproductive functions of the offspring. Altogether, an interaction between inappropriate maternal nutrition (excess or reduced nutritional intake, micronutrient unbalance, or alcohol intake) and reproductive maturation of the offspring has been shown in a majority of experiments as summarized in this review. The exact processes through which maternal nutrition or maternal environment affect reproductive function in the offspring remain unclear but epigenetic modifications are a clear link. Further studies are needed to better understand the mechanisms involved, identify the crucial critical periods, and prevent or treat the adverse effects.

Epigenetic control of development and expression of quantitative traits

In recent years, it has become increasingly clear that epigenetic regulation of gene expression is critical during embryo development and subsequently during pre- and post-natal life. The phenotype of an individual is the result of complex interactions between genotype and current, past and ancestral environment leading to a lifelong remodelling of its epigenome. Practically, if the genome was compared with the hardware in a computer, the epigenome would be the software that directs the computers operation. This review points to the importance of epigenetic processes for genome function in various biological processes, such as embryo development and the expression of quantitative traits.

Sex in basic research – Concepts in the cardiovascular field

Women and men, female and male animals and cells are biologically different, and acknowledgement of this fact is critical to advancing medicine. However, incorporating concepts of sex-specific analysis in basic research is largely neglected, introducing bias into translational findings, clinical concepts and drug development. Research funding agencies recently approached these issues but implementation of policy changes in the scientific community is still limited, probably due to deficits in concepts, knowledge and proper methodology. This expert review is based on the EUGenMed project (www.eugenmed.eu) developing a roadmap for implementing sex and gender in biomedical and health research. For sake of clarity and conciseness, examples are mainly taken from the cardiovascular field that may serve as a paradigm for others, since a significant amount of knowledge how sex and oestrogen determine the manifestation of many cardiovascular diseases (CVD) has been accumulated. As main concepts for implementation of sex in basic research, the study of primary cell and animals of both sexes, the study of the influence of genetic vs. hormonal factors and the analysis of sex chromosomes and sex specific statistics in genome wide association studies (GWAS) are discussed. The review also discusses methodological issues, and analyses strength, weaknesses, opportunities and threats in implementing sex-sensitive aspects into basic research.

[The new paradigm of the developmental origin of health and diseases (DOHaD)--Epigenetics and environment: evidence and missing links].

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.

Épigénétique et réponses transgénérationnelles aux impacts de l’environnement - Des faits aux lacunes

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.

[Epigenetics and Nutrition: maternal nutrition impacts on placental development and health of offspring].

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.

Chapter 20 – Sexual Dimorphism and DOHaD through the Lens of Epigenetics: Genetic, Ancestral, Developmental, and Environmental Origins from Previous to the Next Generation(s)

There is increasing interest in sex-specific nongenetic and noncultural mechanisms transferring a memory of parental exposure to various environments and determining the reactivity of subsequent generations to their environment during their lifetimes. The epigenetic origins of sexual dimorphism are due not only to the chromosomal sex (XX or XY) at conception prior to gonad differentiation, but later on, to a complex intermingling of both hormones and X and Y genes regulating autosomal genes. Sexual dimorphism may also date back to the sex of ancestors who experienced exposure to different environmental factors and transmitted their “imprint” in a sex-specific manner, either through the maternal or paternal lineage or both, and in a manner that may also depend on the sex of the offspring. Observed sexual dimorphism is the result of a subtle entanglement of different epigenetic and other factors and how and when early and life-long environmental exposures interact with them, leading to specific responses, outcomes, and persistence for men and women.