Screening for rare epigenetic variations in autism and schizophrenia

Additional evidence that rare epivariations likely contribute to the mutational spectra underlying neurodevelopmental disorders

2019 Study Abstract

While many studies have led to the identification of rare sequence variants linked with susceptibility to autism and schizophrenia, the contribution of rare epigenetic variations (epivariations) in these disorders remains largely unexplored.

Previously we presented evidence that epivariations occur relatively frequently in the human genome, and likely contribute to a subset of congenital and neurodevelopmental disorders through the disruption of dosage-sensitive genes.

Here we extend this approach, studying methylation profiles from 297 samples with autism and 767 cases with schizophrenia, identifying 84 and 268 rare epivariations in these two cohorts, respectively, that were absent from 4,860 population controls.

We observed multiple features associated with these epivariations that support their pathogenic relevance, including

  1. a significant enrichment for epivariations in schizophrenic individuals at genes previously linked with schizophrenia,
  2. increased brain expression of genes associated with epivariations found in autism cases compared with controls,
  3. in autism families, a significant excess of epivariations found specifically in affected versus unaffected sibs,
  4. Gene Ontology terms linked with epivariations found in autism, including “D1 dopamine receptor binding.”

Our study provides additional evidence that rare epivariations likely contribute to the mutational spectra underlying neurodevelopmental disorders. Image credit Brigham and Women’s Hospital.

DES DIETHYLSTILBESTROL RESOURCES

Effects on offspring of epigenetic inheritance via sperm

Sperm-inherited H3K27me3 impacts offspring transcription and development in C. elegans

In experiments with worms, researchers showed that epigenetic marks on sperm chromosomes affect gene expression and development in offspring.

2019 Study Abstract

Paternal epigenetic inheritance is gaining attention for its growing medical relevance. However, the form in which paternal epigenetic information is transmitted to offspring and how it influences offspring development remain poorly understood.

Here we show that in C. elegans, sperm-inherited chromatin states transmitted to the primordial germ cells in offspring influence germline transcription and development. We show that sperm chromosomes inherited lacking the repressive histone modification H3K27me3 are maintained in that state by H3K36me3 antagonism. Inheritance of H3K27me3-lacking sperm chromosomes results in derepression in the germline of somatic genes, especially neuronal genes, predominantly from sperm-inherited alleles.

This results in germ cells primed for losing their germ cell identity and adopting a neuronal fate. These data demonstrate that histone modifications are one mechanism through which epigenetic information from a father can shape offspring gene expression and development.

Reference. Press release.

Offspring whose mothers experienced early life febrile seizures display long term memory deficits

Prolonged febrile seizures induce inheritable memory deficits in rats through DNA methylation

2018 Summary

Aims:
Febrile seizures (FSs) are the most common types of seizures in young children. However, little is known whether the memory deficits induced by early‐life FSs could transmit across generations or not.

Methods:
The memory functions of different generations of FS rats were behaviorally evaluated by morris water maze, inhibitory avoidance task, and contextual fear conditioning task. Meanwhile, molecular biology and pharmacological methods were used to investigate the role of DNA methylation in transgenerational transmission of memory defects.

Results:
Prolonged FSs in infant rats resulted in memory deficits in adult and transgenerationally transmitted to next generation, which was mainly through mothers. For these two generations, DNA methyltransferase (DNMT) was upregulated, leading to transcriptional inhibition of the synaptic plasticity protein reelin but not the memory suppressor protein phosphatase. DNMT inhibitors prevented the high expression of DNMT and hypermethylation of reelin gene and reversed the transgenerationally memory deficits. In addition, enriched environment in juvenile rats rescued memory deficits induced by prolonged FSs.

Conclusions:
Our study demonstrated early experience of prolonged FSs led to memory deficits in adult rats and their unaffected offspring, which involved epigenetic mechanisms, suggesting early environmental experiences had a significant impact on the transgenerational transmission of neurological diseases.

The negative impact of the environment on methylation/epigenetic marking in gametes and embryos

A plea for action to protect the fertility of future generations, 17 January 2019

Abstract

Life expectancy has increased since World War II and this may be attributed to several aspects of modern lifestyles. However, now we are faced with a downturn, which seems to be the result of environmental issues. This paradigm is paralleled with a reduction in human fertility: decreased sperm quality and increased premature ovarian failure and diminished ovarian reserve syndromes.

Endocrine Disruptor Compounds (EDCs) and other toxic chemicals: herbicides, pesticides, plasticizers, to mention a few, are a rising concern in today environment. Some of these are commonly used in the domestic setting: cleaning material and cosmetics and they have a known impact on epigenesis and imprinting via perturbation of methylation processes. Pollution from Poly Aromatic Hydrocarbons (PAH), particulate matter (PM), <10 and <2.5 μm and ozone, released into the air all affect fertility. Poor food processing management is a source DNA adducts formation, impairing gametes quality. An important question to be answered is that of nanoparticles (NPs) that are present in food and which are thought to induce oxidative stress. Now is the time to take a step backwards. Global management of the environment and food production is required urgently in order to protect the fertility of future generations.

Reference.

DES and the GENES

Genomic imprinting disorders

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

The exposome : can we measure of all the exposures of an individual in a lifetime and how they relate to health ?

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.

More Information

  • 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.

Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray Syndrome

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.

Abstract

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.

EDCs potential long-lasting effects on children’s neurodevelopment

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.

Summary

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.

Can the most frequently used anaesthetic in paediatrics affect the next generation ?

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

Background
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.

Methods
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.

Results
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.

Conclusions
Neonatal exposure to sevoflurane can affect the next generation of males through epigenetic modification of Kcc2 expression, while F1 females are at diminished risk.