Environment-sensitive epigenetics and the heritability of complex diseases

Genome-wide association studies have thus far failed to explain the observed heritability of complex human diseases. This is referred to as the "missing heritability" problem. However, these analyses have usually neglected to consider a role for epigenetic variation, which has been associated with many human diseases. We extend models of epigenetic inheritance to investigate whether environment-sensitive epigenetic modifications of DNA might explain observed patterns of familial aggregation. We find that variation in epigenetic state and environmental state can result in highly heritable phenotypes through a combination of epigenetic and environmental inheritance. These two inheritance processes together can produce familial covariances significantly higher than those predicted by models of purely epigenetic inheritance and similar to those expected from genetic effects. The results suggest that epigenetic variation, inherited both directly and through shared environmental effects, may make a key contribution to the missing heritability.     

Prospects for incorporation of epigenetic biomarkers in human health and environmental risk assessment of chemicals

Epigenetic mechanisms have gained relevance in human health and environmental studies, due to their pivotal role in disease, gene × environment interactions and adaptation to environmental change and/or contamination. Epigenetic mechanisms are highly responsive to external stimuli and a wide range of chemicals has been shown to determine specific epigenetic patterns in several organisms. Furthermore, the mitotic/meiotic inheritance of such epigenetic marks as well as the resulting changes in gene expression and cell/organismal phenotypes has now been demonstrated. Therefore, epigenetic signatures are interesting candidates for linking environmental exposures to disease as well as informing on past exposures to stressors. Accordingly, epigenetic biomarkers could be useful tools in both prospective and retrospective risk assessment but epigenetic endpoints are currently not yet incorporated into risk assessments. Achieving a better understanding on this apparent impasse, as well as identifying routes to promote the application of epigenetic biomarkers within environmental risk assessment frameworks are the objectives of this review. We first compile evidence from human health studies supporting the use of epigenetic exposure‐associated changes as reliable biomarkers of exposure. Then, specifically focusing on environmental science, we examine the potential and challenges of developing epigenetic biomarkers for environmental fields, and discuss useful organisms and appropriate sequencing techniques to foster their development in this context. Finally, we discuss the practical incorporation of epigenetic biomarkers in the environmental risk assessment of chemicals, highlighting critical data gaps and making key recommendations for future research within a regulatory context.     

昆虫滞育表观遗传调控的研究进展

滞育是昆虫躲避不良环境的一种策略,对延续昆虫种群具有重要意义.特别是昆虫的兼性滞育,能够受环境的周期性季节变化影响,表观遗传可能在其中扮演重要角色.表观遗传是不依赖DNA序列改变所产生的可遗传变异,包括DNA、RNA、蛋白质和染色质水平上的各种表观遗传调控过程,可能参与生物的发育可塑性.昆虫滞育表观遗传调控主要包括两个...     

Biological memories of past environments: Epigenetic pathways to health disparities

Human health tends to mirror gradients in social standing related to class, ethnicity and race. Past research in the social sciences suggests that environmental experiences related to social status contribute to these disparities, but the underlying biological mechanisms are only partially understood. Here, we review research related to three domains of environmental exposure that point to epigenetic contributions to health disparities: nutrition, psychosocial stress, and environmental toxicant exposure. Each exposure has effects that may persist across the life course and in some instances may be transmitted to offspring via epigenetic inheritance. Since epigenetic markings provide a "memory" of past experiences, minimizing future disparities in health will be partially contingent upon our ability to address inequality in the current environment. We suggest that future research in environmental epigenetics focus on establishing the reversibility of stress-induced epigenetic modifications, and also on identifying positive epigenetic effects of environmental enrichment.     

表观遗传跨代继承表型研究进展

表观基因组在配子发生和早期胚胎发育中经历一个重编程过程。因此, 人们认为表观遗传信息不可能代间传递。表观遗传跨代继承表型的出现, 说明某些表观遗传标志可能逃脱了重编程。尽管该观点尚存争议, 但日益增多的实验证据表明表观遗传记忆确实存在于哺乳动物中。由于表观遗传修饰具有可逆性, 表观基因组易受各种环境因子(如化学物质、营养和行为等)的影响而改变。因此, 表观基因组提供了跨代传递环境影响的可能机制。文章介绍了表观遗传跨代继承表型的概念, 论述了表观遗传重编程和表观遗传信息跨代传递的分子机制, 列举了一些环境因子与表观遗传跨代继承性疾病。     

Environmental epigenetic modifications and reprogramming-recalcitrant genes

The term “environmental epigenetic modifications” refers to alterations in phenotype triggered by environmental stimuli via epigenetic mechanisms. Epidemiologic and animal model studies show that a subset of such environmental epigenetic marks may affect susceptibility to chronic diseases. A growing body of evidence regarding incompleteness of reprogramming indicates that the potential retention of pathogenic environmental epigenetics in human induced pluripotent stem cells (iPSCs) should be seriously considered. Given this possibility, the optimization of methods for the generation of human induc pluripotent stem cells may require the identification of epigenetically appropriate somatic cell sources. Similarly, techniques for controlling epigenetic modification by environmental factors may also play a critical role in the development of epigenetically stable sources of pluripotent stem cells.     

Twin-Based DNA Methylation Analysis Takes the Center Stage of Studies of Human Complex Diseases

The etiology of complex diseases is characterized by the interaction between the genome and environmental conditions and the interface of epigenetics may be a central mechanism. Current technologies already allow us high-throughput profiling of epigenetic patterns at genome level. However, our understanding of the epigenetic processes remains limited. Twins are special samples in genetic studies due to their genetic similarity and rearing-environment sharing. In the past decades, twins have made a great contribution in dissecting the genetic and environmental contributions to human diseases and complex traits. In the era of functional genomics, the valuable samples of twins are helping to bridge the gap between gene activity and environmental conditions through epigenetic mechanisms unlimited to DNA sequence variations. We review the recent progresses in using twins to study disease-related molecular epigenetic phenotypes and link them with environmental exposures especially early life events. Various study designs and application issues will be highlighted and discussed with aim at making uses of twins in assessing the environmental impact on epigenetic changes during the development of complex diseases.     

Chromatin modifications and remodeling in plant abiotic stress responses

Sensing environmental changes and initiating a gene expression response are important for plants as sessile autotrophs. The ability of epigenetic status to alter rapidly and reversibly could be a key component to the flexibility of plant responses to the environment. The involvement of epigenetic mechanisms in the response to environmental cues and to different types of abiotic stresses has been documented. Different environmental stresses lead to altered methylation status of DNA as well as modifications of nucleosomal histones. Understanding how epigenetic mechanisms are involved in plant response to environmental stress is highly desirable, not just for a better understanding of molecular mechanisms of plant stress response but also for possible application in the genetic manipulation of plants. In this review, we highlight our current understanding of the epigenetic mechanisms of chromatin modifications and remodeling, with emphasis on the roles of specific modification enzymes and remodeling factors in plant abiotic stress responses. This article is part of a Special Issue entitled: Plant gene regulation in response to abiotic stress.     

What obesity research tells us about epigenetic mechanisms

The pathophysiology of obesity is extremely complex and is associated with extensive gene expression changes in tissues throughout the body. This situation, combined with the fact that all gene expression changes are thought to have associated epigenetic changes, means that the links between obesity and epigenetics will undoubtedly be vast. Much progress in identifying epigenetic changes induced by (or inducing) obesity has already been made, with candidate and genome-wide approaches. These discoveries will aid the clinician through increasing our understanding of the inheritance, development and treatment of obesity. However, they are also of great value for epigenetic researchers, as they have revealed mechanisms of environmental interactions with epigenetics that can produce or perpetuate a disease state. Here, we will review the evidence for four mechanisms through which epigenetics contributes to obesity: as downstream effectors of environmental signals; through abnormal global epigenetic state driving obesogenic expression patterns; through facilitating developmental programming and through transgenerational epigenetic inheritance.     

Genetic architecture,epigenetic influence and environment exposure in the pathogenesis of Autism

Autism spectrum disorder(ASD) is a spectral neurodevelopment disorder affecting approximately 1% of the population. ASD is characterized by impairments in reciprocal social interaction, communication deficits and restricted patterns of behavior. Multiple factors, including genetic/genomic, epigenetic/epigenomic and environmental, are thought to be necessary for autism development. Recent reviews have provided further insight into the genetic/genomic basis of ASD. It has long been suspected that epigenetic mechanisms, including DNA methylation, chromatin structures and long non-coding RNAs may play important roles in the pathology of ASD. In addition to genetic/genomic alterations and epigenetic/epigenomic influences, environmental exposures have been widely accepted as an important role in autism etiology, among which immune dysregulation and gastrointestinal microbiota are two prominent ones.     

Genome‐wide epigenetic isolation by environment in a widespread Anolis lizard

Epigenetic changes can provide a pathway for organisms to respond to local environmental conditions by influencing gene expression. However, we still know little about the spatial distribution of epigenetic variation in natural systems, how it relates to the distribution of genetic variation and the environmental structure of the landscape, and the processes that generate and maintain it. Studies examining spatial patterns of genetic and epigenetic variation can provide valuable insights into how ecological and population processes contribute to epigenetic divergence across heterogeneous landscapes. Here, we perform a comparative analysis of spatial genetic and epigenetic variation based on 8,459 single nucleotide polymorphisms (SNPs) and 8,580 single methylation variants (SMVs) from eight populations of the Puerto Rican crested anole, Anolis cristatellus, an abundant lizard in the adaptive radiations of anoles on the Greater Antilles that occupies a diverse range of habitats. Using generalized dissimilarity modelling and multiple matrix regression, we found that genome‐wide epigenetic differentiation is strongly correlated with environmental divergence, even after controlling for the underlying genetic structure. We also detected significant associations between key environmental variables and 96 SMVs, including 42 located in promoter regions or gene bodies. Our results suggest an environmental basis for population‐level epigenetic differentiation in this system and contribute to better understanding how environmental gradients structure epigenetic variation in nature.     

表观遗传调控植物响应非生物胁迫的研究进展

植物的生长发育容易受到外界环境变化的影响。非生物胁迫发生时, 表观遗传机制对胁迫应答基因的表达调控发挥了十分重要的作用。近年来, 调控植物非生物胁迫应答的表观遗传机制研究取得了一系列重要进展, 为进一步深入解析植物响应非生物胁迫的分子机制奠定了基础。该文对DNA甲基化修饰、组蛋白修饰、染色质重塑和非编码RNA等主要表观遗传调控方式在植物响应非生物胁迫中的作用进行了简要综述。     

Environmental exposure and mitochondrial epigenetics: study design and analytical challenges

The environment can influence human health and disease in many harmful ways. Many epidemiological studies have been conducted with the aim of elucidating the association between environmental exposure and human disease at the molecular and pathological levels, and such associations can often be through induced epigenetic changes. One such mechanism for this is through environmental factors increasing oxidative stress in the cell, and this stress can subsequently lead to alterations in DNA molecules. The two cellular organelles that contain DNA are the nucleus and mitochondria, and the latter are particularly sensitive to oxidative stress, with mitochondrial functions often disrupted by increased stress. There has been a substantial increase over the past decade in the number of epigenetic studies investigating the impact of environmental exposures upon genomic DNA, but to date there has been insufficient attention paid to the impact upon mitochondrial epigenetics in studying human disease with exposure to environment. Here, in this review, we will discuss mitochondrial epigenetics with regard to epidemiological studies, with particular consideration given to study design and analytical challenges. Furthermore, we suggest future directions and perspectives in the field of mitochondrial epigenetic epidemiological studies.     

Epigenetics, a mode for plants to respond to abiotic stresses

Epigenetics has been becoming a hot topic in recent years.It can be mechanisms that regulate gene expression without changing DNA base sequence.In plants epigenetic regulation has been implicated to be...     

Epigenetic mechanisms in hepatocellular carcinoma: how environmental factors influence the epigenome

Epigenetic mechanisms maintain heritable changes in gene expression and chromatin organization over many cell generations. Importantly, deregulated epigenetic mechanisms play a key role in a wide range of human malignancies, including liver cancer. Hepatocellular carcinoma (HCC), which originates from the hepatocytes, is by far the most common liver cancer, with rates and aetiology that show considerable geographic variation. Various environmental agents and lifestyles known to be risk factors for HCC (such as infection by hepatitis B virus (HBV) and hepatitis C virus (HCV), chronic alcohol intake, and aflatoxins) are suspected to promote its development by eliciting epigenetic changes, however the precise gene targets and underlying mechanisms have not been elucidated. Many recent studies have exploited conceptual and technological advances in epigenetics and epigenomics to investigate the role of epigenetic events induced by environmental factors in HCC tumors and non-tumor precancerous (cirrhotic) lesions. These studies have identified a large number of genes and pathways that are targeted by epigenetic deregulation (changes in DNA methylation, histone modifications and RNA-mediated gene silencing) during the development and progression of HCC. Frequent identification of aberrant epigenetic changes in specific genes in cirrhotic tissue is consistent with the notion that epigenetic deregulation of selected genes in pre-malignant lesions precedes and promotes the development of HCC. In addition, several lines of evidence argue that some environmental factors (such as HBV virus) may abrogate cellular defense systems, induce silencing of host genes and promote HCC development via an "epigenetic strategy". Finally, profiling studies reveal that HCC tumors and pre-cancerous lesions may exhibit epigenetic signatures associated with specific risk factors and tumor progression stage. Together, recent evidence underscores the importance of aberrant epigenetic events induced by environmental factors in liver cancer and highlights potential targets for biomarker discovery and future preventive and therapeutic strategies.     

Epigenetic variation associated with responses to different habitats in the context of genetic divergence in Phragmites australis

The mechanisms underlying heritable phenotypic divergence associated with adaptation in response to environmental stresses may involve both genetic and epigenetic variations. Several prior studies have revealed even higher levels of epigenetic variation than genetic variation. However, few population‐level studies have explored the effects of epigenetic variation on species with high levels of genetic diversity distributed across different habitats. Using AFLP and methylation‐sensitive AFLP markers, we tested the hypothesis that epigenetic variation may contribute to differences in plants occupying different habitats when genetic variation alone cannot fully explain adaptation. As a cosmopolitan invasive species, Phragmites australis (common reed) together with high genetic diversity and remarkable adaptability has been suggested as a model for responses to global change and indicators of environmental fluctuations. We found high levels of genetic and epigenetic diversity and significant genetic/epigenetic structure within each of 12 studied populations sampled from four natural habitats of P. australis. Possible adaptive epigenetic variation was suggested by significant correlations between DNA methylation‐based epigenetic differentiation and adaptive genetic divergence in populations across the habitats. Meanwhile, various AMOVAs indicated that some epigenetic differences may respond to various local habitats. A partial Mantel test was used to tease out the correlations between genetic/epigenetic variation and habitat after controlling for the correlation between genetic and epigenetic variations. We found that epigenetic diversity was affected mostly by soil nutrient availability, suggesting that at least some epigenetic differentiation occurred independently of genetic variation. We also found stronger correlations between epigenetic variation and phenotypic traits than between genetic variation and such traits. Overall, our findings indicate that genetically based differentiation correlates with heterogeneous habitats, while epigenetic variation plays an important role in ecological differentiation in natural populations of P. australis. In addition, our results suggest that when assessing global change responses of plant species, intraspecific variation needs to be considered.     

Inherited epigenetic variation--revisiting soft inheritance

Phenotypic variation is traditionally parsed into components that are directed by genetic and environmental variation. The line between these two components is blurred by inherited epigenetic variation, which is potentially sensitive to environmental inputs. Chromatin and DNA methylation-based mechanisms mediate a semi-independent epigenetic inheritance system at the interface between genetic control and the environment. Should the existence of inherited epigenetic variation alter our thinking about evolutionary change?     

Epigenetics in natural animal populations

Phenotypic plasticity is an important mechanism for populations to buffer themselves from environmental change. While it has long been appreciated that natural populations possess genetic variation in the extent of plasticity, a surge of recent evidence suggests that epigenetic variation could also play an important role in shaping phenotypic responses. Compared with genetic variation, epigenetic variation is more likely to have higher spontaneous rates of mutation and a more sensitive reaction to environmental inputs. In our review, we first provide an overview of recent studies on epigenetically encoded thermal plasticity in animals to illustrate environmentally‐mediated epigenetic effects within and across generations. Second, we discuss the role of epigenetic effects during adaptation by exploring population epigenetics in natural animal populations. Finally, we evaluate the evolutionary potential of epigenetic variation depending on its autonomy from genetic variation and its transgenerational stability. Although many of the causal links between epigenetic variation and phenotypic plasticity remain elusive, new data has explored the role of epigenetic variation in facilitating evolution in natural populations. This recent progress in ecological epigenetics will be helpful for generating predictive models of the capacity of organisms to adapt to changing climates.