Lessons on how genome, epigenome and environment interact
2019 Study Abstract
Genomic imprinting, the monoallelic and parent-of-origin-dependent expression of a subset of genes, is required for normal development, and its disruption leads to human disease.
Imprinting defects can involve isolated or multilocus epigenetic changes that may have no evident genetic cause, or imprinting disruption can be traced back to alterations of cis-acting elements or trans-acting factors that control the establishment, maintenance and erasure of germline epigenetic imprints.
Recent insights into the dynamics of the epigenome, including the effect of environmental factors, suggest that the developmental outcomes and heritability of imprinting disorders are influenced by interactions between the genome, the epigenome and the environment in germ cells and early embryos.
This review focuses on imprints that effect essentially permanent and ubiquitous changes on gene expression potential at affected loci, as opposed to tissue-specific or transient changes.
DES and the GENES
Development of exposome correlation globes to map out environment-wide associations
Success in mapping the human genome has fostered the complementary concept of the “exposome“.
The exposome can be defined as the measure of all the exposures of an individual in a lifetime and how those exposures relate to health. An individual’s exposure begins before birth and includes insults from environmental and occupational sources. Understanding how exposures from our environment, diet, lifestyle, etc. interact with our own unique characteristics such as genetics, physiology, and epigenetics impact our health is how the exposome will be articulated.
Exposomics is the study of the exposome and relies on the application of internal and external exposure assessment methods.
2016 Paper Abstract
The exposome concept was defined in 2005 as encompassing all environmental exposures from conception onwards, as a new strategy to evidence environmental disease risk factors. Although very appealing, the exposome concept is challenging in many respects. In terms of assessment, several hundreds of time-varying exposures need to be considered, but increasing the number of exposures assessed should not be done at the cost of increased exposure misclassification. Accurately assessing the exposome currently requires numerous measurements, which rely on different technologies; resulting in an expensive set of protocols. In the future, high-throughput ‘omics technologies may be a promising technique to integrate a wide range of exposures from a small numbers of biological matrices. Assessing the association between many exposures and health raises statistical challenges. Due to the correlation structure of the exposome, existing statistical methods cannot fully and efficiently untangle the exposures truly affecting the health outcome from correlated exposures. Other statistical challenges relate to accounting for exposure misclassification or identifying synergistic effects between exposures. On-going exposome projects are trying to overcome technical and statistical challenges. From a public health perspective, a better understanding of the environmental risk factors should open the way to improved prevention strategies.
2015 Paper Abstract
The environment plays a major role in influencing diseases and health. The phenomenon of environmental exposure is complex and humans are not exposed to one or a handful factors but potentially hundreds factors throughout their lives. The exposome, the totality of exposures encountered from birth, is hypothesized to consist of multiple inter-dependencies, or correlations, between individual exposures. These correlations may reflect how individuals are exposed. Currently, we lack methods to comprehensively identify robust and replicated correlations between environmental exposures of the exposome. Further, we have not mapped how exposures associated with disease identified by environment-wide association studies (EWAS) are correlated with other exposures. To this end, we implement methods to describe a first “exposome globe”, a comprehensive display of replicated correlations between individual exposures of the exposome. First, we describe overall characteristics of the dense correlations between exposures, showing that we are able to replicate 2,656 correlations between individual exposures of 81,937 total considered (3%). We document the correlation within and between broad a priori defined categories of exposures (e.g., pollutants and nutrient exposures). We also demonstrate utility of the exposome globe to contextualize exposures found through two EWASs in type 2 diabetes and all-cause mortality, such as exposure clusters putatively related to smoking behaviors and persistent pollutant exposure. The exposome globe construct is a useful tool for the display and communication of the complex relationships between exposure factors and between exposure factors related to disease status.
- The exposome concept: a challenge and a potential driver for environmental health research, ersjournals, 2016.
- Development of exposome correlation globes to map out environment-wide associations, ncbi, PMC4299925, 2015.
- Exposome and Exposomics, cdc, niosh.
- humanexposomeproject website.
After 60 years, scientists uncover how thalidomide produced birth defects
More than 60 years after the drug thalidomide caused birth defects in thousands of children whose mothers took the drug while pregnant, scientists at Dana-Farber Cancer Institute have solved a mystery that has lingered ever since the dangers of the drug first became apparent: how did the drug produce such severe fetal harm?
ScienceAlert reports, 2 AUG 2018.
Frequently used to treat morning sickness, the drug thalidomide led to the birth of thousands of children with severe birth defects. Despite their teratogenicity, thalidomide and related IMiD drugs are now a mainstay of cancer treatment, however, the molecular basis underlying the pleiotropic biology and characteristic birth defects remains unknown.
Here we show that IMiDs disrupt a broad transcriptional network through induced degradation of several C2H2 zinc finger transcription factors, including SALL4, a member of the spalt-like family of developmental transcription factors.
Strikingly, heterozygous loss of function mutations in SALL4 result in a human developmental condition that phenocopies thalidomide induced birth defects such as absence of thumbs, phocomelia, defects in ear and eye development, and congenital heart disease.
We find that thalidomide induces degradation of SALL4 exclusively in humans, primates and rabbits, but not in rodents or fish, providing a mechanistic link for the species-specific pathogenesis of thalidomide syndrome.
Placental CpG methylation of HPA-axis genes is associated with cognitive impairment at age 10 among children born extremely preterm
2018 Study Highlights
- Placental CpG methylation in relation to cognition at age 10 was evaluated.
- Ten HPA axis-associated genes were associated with cognitive function.
- The transcriptional regulator MECP2 was enriched within the ten HPA axis genes.
- Placental CpG methylation in the context of fetal development is discussed.
- This study relates to the developmental origins of health and disease hypothesis.
The results of this study highlight a set of 10 HPA axis-associated genes that displayed an association between increased placental CpG methylation and either moderate/severe cognitive impairment or low/low normal cognitive function at age 10 years. Many of these genes regulate both placental function and HPA axis function. The identified genes are also known to play integral roles in memory, learning, and the development of psychological disorders and there is evidence that exposure to EDCs may influence their expression as well. Furthermore, given the plasticity of the epigenome during the prenatal period, these alterations could be influenced by exposure to environmental contaminants, including EDCs. Growing research supports that exposure to common EDCs, including estrogenic compound like BPA, may dysregulate several genes involved in regulation of the HPA axis. This work provides a basis for which to subsequently investigate the role of EDCs on the HPA axis. Future work should incorporate exposure data as it relates to epigenetic modifications of the HPA axis-associated genes, as these data could provide more information as to how EDCs mechanistically disrupt the HPA axis and potentially provide biomarkers for exposure and laterlife cognitive impairments in mid-childhood.
How the experiences of previous generations change who we are
Role of epigenetic mechanisms in transmitting the effects of neonatal sevoflurane exposure to the next generation of male, but not female, rats
2018 Study Abstract
Clinical studies report learning disabilities and attention-deficit/hyperactivity disorders in those exposed to general anaesthesia early in life. Rats, primarily males, exposed to GABAergic anaesthetics as neonates exhibit behavioural abnormalities, exacerbated responses to stress, and reduced expression of hypothalamic K+-2Cl− Cl− exporter (Kcc2). The latter is implicated in development of psychiatric disorders, including male predominant autism spectrum disorders. In this study, we tested whether parental early life exposure to sevoflurane, the most frequently used anaesthetic in paediatrics, affects the next generation of unexposed rats.
Offspring (F1) of unexposed or exposed to sevoflurane on postnatal day 5 Sprague-Dawley rats (F0) were subjected to behavioural and brain gene expression evaluations.
Male, but not female, progeny of sevoflurane-exposed parents exhibited abnormalities in behavioural testing and Kcc2 expression. Male F1 rats of both exposed parents exhibited impaired spatial memory and expression of hippocampal and hypothalamic Kcc2. Offspring of only exposed sires had abnormalities in elevated plus maze and prepulse inhibition of startle, but normal spatial memory and impaired expression of hypothalamic, but not hippocampal, Kcc2. In contrast to exposed F0, their progeny exhibited normal corticosterone responses to stress. Bisulphite sequencing revealed increased CpG site methylation in the Kcc2 promoter in F0 sperm and F1 male hippocampus and hypothalamus that was in concordance with the changes in Kcc2 expression in specific F1 groups.
Neonatal exposure to sevoflurane can affect the next generation of males through epigenetic modification of Kcc2 expression, while F1 females are at diminished risk.
Aattention-Deficit/Hyperactivity Disorder Much More Common in Grandchildren of Women Who Were Prescribed the DES Drug in Pregnancy
A cohort study – Association of Exposure to Diethylstilbestrol During Pregnancy With Multigenerational Neurodevelopmental Deficits – published May 21, 2018, shows that prenatal diethylstilbestrol exposure may lead to neurodevelopmental disorders across several generations : DES grandchildren are more likely to be diagnosed with ADHD (36% to 63%).
The audio summary above reviews the cohort study that uses Nurses’ Health Study data to investigate associations between diethylstilbestrol (DES) use in pregnancy and self-reported development of ADHD in grandchildren.
More DES DiEthylStilbestrol Resources
Dr Anne Wautier, Réseau DES France, Forum d’Infertilité 2017
Vidéos en français: Distilbène DES : 60 vidéos à visionner sur YouTube.
Image credit @magicmaman_com.
Le Dr Anne Wautier, gynécologue médicale, aborde de façon très claire (et avec des exemples aidant à la compréhension) des notions complexes telles que : épigénétique, perturbateurs endocriniens, effets transgénérationnels du distilbene DES.
Enregistrement provenant de la 4ème Journée Nationale de l’Infertilité, un forum d’information et d’aide aux personnes infertiles organisé cet automne 2017, Paris 12.
Le Distilbène DES, en savoir plus
- Conséquences du DES en 2017 :
- Epigénétique et générations futures :
- Bibliographie :
The University of Oslo Faculty of Medicine, 2016
How do the identical twins Lucky Lyle and Troubled Tim end up with different personalities? Is it the environment or genes? Or perhaps both?
Video published by The University of Oslo Faculty of Medicine, 29 Jan 2016.
Epigenetics between the generations : we inherit more than just genes
Epigenetic mechanisms modulated by environmental cues such as diet, disease or our lifestyle take a major role in regulating the DNA by switching genes on and off. It has been long debated if epigenetic modifications accumulated throughout the entire life can cross the border of generations and be inherited to children or even grand children. Now researchers from the Max Planck Institute of Immunobiology and Epigenetics in Freiburg show robust evidence that not only the inherited DNA itself but also the inherited epigenetic instructions contribute in regulating gene expression in the offspring. Moreover, the new insights by the Lab of Nicola Iovino describe for the first time biological consequences of this inherited information. The study proves that mother’s epigenetic memory is essential for the development and survival of the new generation.
Gametes carry parental genetic material to the next generation. Stress-induced epigenetic changes in the germ line can be inherited and can have a profound impact on offspring development. However, the molecular mechanisms and consequences of transgenerational epigenetic inheritance are poorly understood. We found that Drosophila oocytes transmit the repressive histone mark H3K27me3 to their offspring. Maternal contribution of the histone methyltransferase Enhancer of zeste, the enzymatic component of Polycomb repressive complex 2, is required for active propagation of H3K27me3 during early embryogenesis. H3K27me3 in the early embryo prevents aberrant accumulation of the active histone mark H3K27ac at regulatory regions and precocious activation of lineage-specific genes at zygotic genome activation. Disruption of the germ line–inherited Polycomb epigenetic memory causes embryonic lethality that cannot be rescued by late zygotic reestablishment of H3K27me3. Thus, maternally inherited H3K27me3, propagated in the early embryo, regulates the activation of enhancers and lineage-specific genes during development.
- Epigenetics between the generations : researchers prove that we inherit more than just genes, Max-Planck-Gesellschaft, July 13, 2017.
- Germ line–inherited H3K27me3 restricts enhancer function during maternal-to-zygotic transition, sciencemag, DOI: 10.1126/science.aam5339, 14 Jul 2017.
- Featured image © MPI of Immunobiology a. Epigenetics / F. Zenk – Egg-cell of a female fruit fly with the egg cell in which H3K27me3 was made visible through green staining. This cell, together with the sperm, will contribute to the formation of the next generation of flies. In the upper right corner, a maternal and paternal pre-nucleus are depicted before their fusion during fertilization. The green colouration of H3K27me3 appears exclusively in the maternal pre-nucleus, indicating that their epigenetic instructions are inherited into the next generation.