Epigenetic modifications and human disease

Epigenetics is one of the most rapidly expanding fields in biology. The recent characterization of a human DNA methylome at single nucleotide resolution, the discovery of the CpG island shores, the finding of new histone variants and modifications, and the unveiling of genome-wide nucleosome positioning maps highlight the accelerating speed of discovery over the past two years. Increasing interest in epigenetics has been accompanied by technological breakthroughs that now make it possible to undertake large-scale epigenomic studies. These allow the mapping of epigenetic marks, such as DNA methylation, histone modifications and nucleosome positioning, which are critical for regulating gene and noncoding RNA expression. In turn, we are learning how aberrant placement of these epigenetic marks and mutations in the epigenetic machinery is involved in disease. Thus, a comprehensive understanding of epigenetic mechanisms, their interactions and alterations in health and disease, has become a priority in biomedical research.     

Synergy of Homocysteine, MicroRNA, and Epigenetics: A Novel Therapeutic Approach for Stroke

Homocysteine (Hcy) is a thiol-containing amino acid formed during methionine metabolism. Elevated level of Hcy is known as hyperhomocysteinemia (HHcy). HHcy is an independent risk factor for cerebrovascular diseases such as stroke, dementia, Alzheimer’s disease, etc. Stroke, which is caused by interruption of blood supply to the brain, is one of the leading causes of death and disability in a number of people worldwide. The HHcy causes an increased carotid artery plaque that may lead to ischemic stroke but the mechanism is currently not well understood. Though mutations or polymorphisms in the key genes of Hcy metabolism pathway have been well elucidated in stroke, emerging evidences suggested epigenetic mechanisms equally play an important role in stroke development such as DNA methylation, chromatin remodeling, RNA editing, noncoding RNAs (ncRNAs), and microRNAs (miRNAs). However, there is no review available yet that describes the role of genetics and epigenetics during HHcy in stroke. The current review highlights the role of genetics and epigenetics in stroke during HHcy and the role of epigenetics in its therapeutics. The review also highlights possible epigenetic mechanisms, potential therapeutic molecules, putative challenges, and approaches to deal with stroke during HHcy.     

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方面：一是表观遗传调控如何响应滞育诱导的环境信号;二是环境信号诱导的表观遗传调控如何作用昆虫滞育。尽管已有报道提示DNA甲基化可以响应光周期信号,组蛋白乙酰化能够耦联昆虫内分泌信号,但表观遗传调控参与昆虫滞育的具体机制尚不完全清楚。表观遗传调控昆虫滞育在不同滞育类型的昆虫中都有报道。对于同一滞育类型,不同表观遗传过程之间可能存在协同,这种协同作用如何响应环境信号,又如何精确调节昆虫滞育仍不得而知。总之,现有研究仅仅展示了表观遗传调控昆虫滞育的可能性,昆虫滞育表观遗传调控的分子机制亟待深入研究,特别是以下几个方面：(1)表观遗传响应滞育诱导环境信号的分子机制研究;(2)表观遗传耦联内分泌调控的分子机制研究;(3)介导表观遗传调控的细胞信号转导研究;(4)表观遗传的协同调控在昆虫滞育中的功能研究。     

Navigating the boundaries between metabolism and epigenetics in trypanosomes

Epigenetic marks enable cells to acquire new biological features that favor their adaptation to environmental changes. These marks are chemical modifications on chromatin-associated proteins and nucleic acids that lead to changes in the chromatin landscape and may eventually affect gene expression. The chemical tags of these epigenetic marks are comprised of intermediate cellular metabolites. The number of discovered associations between metabolism and epigenetics has increased, revealing how environment influences gene regulation and phenotype diversity. This connection is relevant to all organisms but underappreciated in digenetic parasites, which must adapt to different environments as they progress through their life cycles. This review speculates and proposes associations between epigenetics and metabolism in trypanosomes, which are protozoan parasites that cause human and livestock diseases.     

CpG Island Hypermethylation of Tumor Suppressor microRNAs in Human Cancer

In the last few years, microRNAs have started a revolution in molecular biology and emerged as key players in the cancer process. For these reasons, it is extremely important to understand the physiological and disease-associated mechanisms underlying the regulation of these small, single-stranded RNAs. Thus, it was merely a matter of time before microRNAs and epigenetics coincided. In cancer, aberrant DNA hypermethylation of tumor suppressor genes, global genomic DNA hypomethylation, and disruption of the histone modification patterns are the main epigenetic alterations, and have consequently been widely studied. Some microRNAs are downregulated in cancer and act as bona fide tumor suppressor genes, and this knowledge led to the proposal of the hypothesis that miRNAs could be silenced by epigenetic mechanisms. It has recently been shown that miR-127 and miR-124a, two putative tumor suppressor miRNAs, are methylated in tumor cells. Epigenomic tools can be effectively used in the search for new methylated tumor suppressor microRNAs. Furthermore, this aberrant methylation can be reversed by epigenetic drugs, such as DNA demethylating agents and histone deacetylase inhibitors, restoring microRNA expression levels and reverting the tumoral phenotype. In the coming years we will come to realize more fully the relevance of this expected encounter between two forces – epigenetics and microRNAs – that are currently at the forefront of biology.     

Non-coding RNAs, epigenetics and complexity

Several aspects of epigenetics are strongly linked to non-coding RNAs, especially small RNAs that can direct the cytosine methylation and histone modifications that are implicated in gene expression regulation in complex organisms. A fundamental characteristic of epigenetics is that the same genome can show alternative phenotypes, which are based in different epigenetic states. Some of the most studied complex epigenetic phenomena including transposon activity and silencing recently exemplified by piRNAs (piwi-interacting RNAs), position effect variegation, X-chromosome inactivation, parental imprinting, and paramutation have direct or indirect participation of an RNA component. Conceivably, most of the non-coding RNAs with no described function yet, are players in epigenetic mechanisms that are still not completely understood. In that regard, RNAs were recently implicated in new mechanisms of genetic information transfer in yeast, plants and mice. In this review article, the hypothesis that non-coding RNAs might be the main component of complex organisms acquired during evolution will be explored. The question of how evolutionary theories have been challenged by these molecules in association with epigenetic mechanisms will also be discussed here.     

A genomic point-of-view on environmental factors influencing the human brain methylome

The etiologic paradigm of complex human disorders such as autism is that genetic and environmental risk factors are independent and additive, but the interactive effects at the epigenetic interface are largely ignored. Genomic technologies have radically changed perspective on the human genome and how the epigenetic interface may impact complex human disorders. Here, I review recent genomic, environmental and epigenetic findings that suggest a new paradigm of “integrative genomics” in which genetic variation in genomic size may be impacted by dietary and environmental factors that influence the genomic saturation of DNA methylation. Human genomes are highly repetitive, but the interface of large-scale genomic differences with environmental factors that alter the DNA methylome such as dietary folate is under-explored. In addition to obvious direct effects of some environmental toxins on the genome by causing chromosomal breaks, non-mutagenic toxin exposures correlate with DNA hypomethylation that can lead to rearrangements between repeats or increased retrotransposition. Since human neurodevelopment appears to be particularly sensitive to alterations in epigenetic pathways, a further focus will be on how developing neurons may be particularly impacted by even subtle alterations to DNA methylation and proposing new directions towards understanding the quixotic etiology of autism by integrative genomic approaches.Key words: DNA methylation, copy number variation, autism, neurodevelopment, genomics, epigenomics, epigenetics, folate, folic acid, environmental exposures, Alu, MeCP2, LINE-1     

Chromatin remodeling and human disease

In the past few years, there has been a nascent convergence of scientific understanding of inherited human diseases with epigenetics. Identified epigenetic processes involved in human disease include covalent DNA modifications, covalent histone modifications, and histone relocation. Each of these processes influences chromatin structure and thereby regulates gene expression and DNA methylation, replication, recombination, and repair. The importance of these processes for nearly all aspects of normal growth and development is illustrated by the array of multi-system disorders and neoplasias caused by their dysregulation.     

Epigenetic determinism in science and society

The epigenetic “revolution” in science cuts across many disciplines, and it is now one of the fastest-growing research areas in biology. Increasingly, claims are made that epigenetics research represents a move away from the genetic determinism that has been prominent both in biological research and in understandings of the impact of biology on society. We discuss to what extent an epigenetic framework actually supports these claims. We show that, in contrast to the received view, epigenetics research is often couched in language as deterministic as genetics research in both science and the popular press. We engage the rapidly emerging conversation about the impact of epigenetics on public discourse and scientific practice, and we contend that the notion of epigenetic determinism – or the belief that epigenetic mechanisms determine the expression of human traits and behaviors – matters for understandings of the influence of biology and society on population health.     

Epigenetic inheritance,prions and evolution

The field of epigenetics has grown explosively in the past two decades or so. As currently defined, epigenetics deals with heritable, metastable and usually reversible changes that do not involve alterations in DNA sequence, but alter the way that information encoded in DNA is utilized. The bulk of current research in epigenetics concerns itself with mitotically inherited epigenetic processes underlying development or responses to environmental cues (as well as the role of mis-regulation or dys-regulation of such processes in disease and ageing), i.e., epigenetic changes occurring within individuals. However, a steadily growing body of evidence indicates that epigenetic changes may also sometimes be transmitted from parents to progeny, meiotically in sexually reproducing organisms or mitotically in asexually reproducing ones. Such transgenerational epigenetic inheritance (TEI) raises obvious questions about a possible evolutionary role for epigenetic ‘Lamarckian’ mechanisms in evolution, particularly when epigenetic modifications are induced by environmental cues. In this review I attempt a brief overview of the periodically reviewed and debated ‘classical’ TEI phenomena and their possible implications for evolution. The review then focusses on a less-discussed, unique kind of protein-only epigenetic inheritance mediated by prions. Much remains to be learnt about the mechanisms, persistence and effects of TEI. The jury is still out on their evolutionary significance and how these phenomena should be incorporated into evolutionary theory, but the growing weight of evidence indicates that likely evolutionary roles for these processes need to be seriously explored.     

Neural and behavioral epigenetics; what it is,and what is hype

The ability to examine epigenetic mechanisms in the brain has become readily available over the last 20 years. This has led to an explosion of research and interest in neural and behavioral epigenetics. Of particular interest to researchers, and indeed the lay public, is the possibility that epigenetic processes, such as changes in DNA‐methylation and histone modification, may provide a biochemical record of environmental effects. This has led to some fascinating insights into how molecular changes in the brain can control behavior. However, some of this research has also attracted controversy and, as is dealt with here, some overblown claims. This latter problem is partly linked to the shifting sands of what is defined as ‘epigenetics’. In this review, I provide an overview of what exactly epigenetics is, and what is hype, with the aim of opening up a debate as to how this exciting field moves forward.     

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.     

Epigenetic events in mammalian germ-cell development: reprogramming and beyond

The epigenetic profile of germ cells, which is defined by modifications of DNA and chromatin, changes dynamically during their development. Many of the changes are associated with the acquisition of the capacity to support post-fertilization development. Our knowledge of this aspect has greatly increased- for example, insights into how the re-establishment of parental imprints is regulated. In addition, an emerging theme from recent studies is that epigenetic modifiers have key roles in germ-cell development itself--for example, epigenetics contributes to the gene-expression programme that is required for germ-cell development, regulation of meiosis and genomic integrity. Understanding epigenetic regulation in germ cells has implications for reproductive engineering technologies and human health.