Master and servant: epigenetic deregulations as a cause and a consequence of cancer

The processes that affect the activity of the genome in a heritable manner without changing its sequence are called epigenetic. Here we review the modes of epigenetic gene regulation, and describe their alterations in cancer. We show how these mechanisms are interdependent, and how they intersect with genetic mutations. We argue that epigenetic abnormalities can occur both as a cause, and as a consequence of cancer. Indeed, oncogenic transformation can deeply alter the epigenetic information contained in the pattern of DNA methylation or histone tail modification. Conversely, epigenetic dysfunctions can drive cellular transformation. We then touch on some practical consequences of the prominence of epigenetic alterations in cancer : increasing knowledge of this field has allowed the development of a new generation of diagnostic tools and therapeutic avenues. Finally we point out that epigenetic phenomena may act as sensors that link environmental conditions to cancer.     

Epigenetic mechanisms in schizophrenia

Epidemiological research suggests that both an individual's genes and the environment underlie the pathophysiology of schizophrenia. Molecular mechanisms mediating the interplay between genes and the environment are likely to have a significant role in the onset of the disorder. Recent work indicates that epigenetic mechanisms, or the chemical markings of the DNA and the surrounding histone proteins, remain labile through the lifespan and can be altered by environmental factors. Thus, epigenetic mechanisms are an attractive molecular hypothesis for environmental contributions to schizophrenia. In this review, we first present an overview of schizophrenia and discuss the role of nature versus nurture in its pathology, where ‘nature’ is considered to be inherited or genetic vulnerability to schizophrenia, and ‘nurture’ is proposed to exert its effects through epigenetic mechanisms. Second, we define DNA methylation and discuss the evidence for its role in schizophrenia. Third, we define posttranslational histone modifications and discuss their place in schizophrenia. This research is likely to lead to the development of epigenetic therapy, which holds the promise of alleviating cognitive deficits associated with schizophrenia.     

Epigenetic marks in melanoma

Melanoma is a highly heterogeneous cancer that comes in different flavors (lentigo maligna melanoma, superficial spreading melanoma, nodular melanoma, acral lentiginous/mucosal melanoma and other less common subtypes including malignant cellular blue nevus, desmoplastic melanoma, nevoid melanoma, and animal‐type melanoma) and colors (black/bluish or unpigmented). Pathologists have known for many years that melanoma displays notable changes in the nuclear architecture including thick chromatic rims, presence of mitosis, nuclear grooves, and more. It is now evident from other cancers that such changes reflect not only genomic alterations but also non‐genomic changes in both the structure of DNA and the structure of chromatin to which the DNA is bound (nucleosomes). Although aberrant gene expression resulting from DNA methylation has been known for many years, genome alterations resulting from histone modifications became evident in the current decade. In prostate and other cancers, some histone marks have clinical diagnostic and/or prognostic value. Here, we review the current data on epigenetic research in melanoma skin cancers, discuss ways to modify the epigenetic landscape of melanoma for inhibiting its growth, and propose strategies for identifying novel melanoma markers.     

癌症中的表观遗传变化

DNA与组蛋白上的共价标记如何参与癌细胞的产生与扩散,这项研究同时带来了新的治疗策略。     

Epigenetic mechanisms in cognition

Although the critical role for epigenetic mechanisms in development and cell differentiation has long been appreciated, recent evidence reveals that these mechanisms are also employed in postmitotic neurons as a means of consolidating and stabilizing cognitive-behavioral memories. In this review, we discuss evidence for an "epigenetic code" in the central nervous system that mediates synaptic plasticity, learning, and memory. We consider how specific epigenetic changes are regulated and may interact with each other during memory formation and how these changes manifest functionally at the cellular and circuit levels. We also describe a central role for mitogen-activated protein kinases in controlling chromatin signaling in plasticity and memory. Finally, we consider how aberrant epigenetic modifications may lead to cognitive disorders that affect learning and memory, and we review the therapeutic potential of epigenetic treatments for the amelioration of these conditions.     

Epigenetic heredity in evolution

We discuss the role of cell memory in heredity and evolution. We describe the properties of the epigenetic inheritance systems (EISs) that underlie cell memory and enable environmentally and developmentally induced cell phenotypes to be transmitted in cell lineages, and argue that transgenerational epigenetic inheritance is an important and neglected part of heredity. By looking at the part EISs have played in the evolution of multicellularity, ontogeny, chromosome organization, and the origin of some post-mating isolating mechanisms, we show how considering the role of epigenetic inheritance can sometimes shed light on major evolutionary processes.     

Epigenetic inheritance in evolution

We discuss the role of cell memory in heredity and evolution. We describe the properties of the epigenetic inheritance systems (EISs) that underlie cell memory and enable environmentally and developmentally induced cell phenotypes to be transmitted in cell lineages, and argue that transgenerational epigenetic inheritance is an important and neglected part of heredity. By looking at the part EISs have played in the evolution of multicellularity, ontogeny, chromosome organization, and the origin of some post-mating isolating mechanisms, we show how considering the role of epigenetic inheritance can sometimes shed light on major evolutionary processes.     

Epigenetic control

Epigenetics refers to mitotically and/or meiotically heritable variations in gene expression that are not caused by changes in DNA sequence. Epigenetic mechanisms regulate all biological processes from conception to death, including genome reprogramming during early embryogenesis and gametogenesis, cell differentiation and maintenance of a committed lineage. Key epigenetic players are DNA methylation and histone post‐translational modifications, which interplay with each other, with regulatory proteins and with non‐coding RNAs, to remodel chromatin into domains such as euchromatin, constitutive or facultative heterochromatin and to achieve nuclear compartmentalization. Besides epigenetic mechanisms such as imprinting, chromosome X inactivation or mitotic bookmarking which establish heritable states, other rapid and transient mechanisms, such as histone H3 phosphorylation, allow cells to respond and adapt to environmental stimuli. However, these epigenetic marks can also have long‐term effects, for example in learning and memory formation or in cancer. Erroneous epigenetic marks are responsible for a whole gamut of diseases including diseases evident at birth or infancy or diseases becoming symptomatic later in life. Moreover, although epigenetic marks are deposited early in development, adaptations occurring through life can lead to diseases and cancer. With epigenetic marks being reversible, research has started to focus on epigenetic therapy which has had encouraging success. As we witness an explosion of knowledge in the field of epigenetics, we are forced to revisit our dogma. For example, recent studies challenge the idea that DNA methylation is irreversible. Further, research on Rett syndrome has revealed an unforeseen role for methyl‐CpG‐binding protein 2 (MeCP2) in neurons. J. Cell. Physiol. 219: 243–250, 2009. © 2009 Wiley‐Liss, Inc.     

Epigenetic Effects in Livestock Breeding

Epigenetic effects are considered as a mechanism of the emergence of new inherited traits with their transmission between generations through meiosis. Modern genomic evaluation does not explain the entire phenotypic variance of traits. It is quite obvious that a significant part of the unaccounted dispersion reflects epigenetic effects carried out through DNA methylation, histone and chromatin modifications, and activity of noncoding types of RNA. Epigenetic effects could potentially be used in breeding programs. The obtained data testify to the significant role of epigenetic factors in the expression of imprinting genes, cellular processes, development of muscle tissue, and fat metabolism in animals. The ability of various additives in the diet to induce epigenetic modifications with phenotypic variability has been convincingly proven. However, there are still many contradictions and limitations in the justification of the hereditary component of epigenetics for introduction into animal breeding. Development of modern technologies, such as chromatin immunoprecipitation with microchips of DNA (ChIP-Chip), next-generation sequencing (ChIP-Seq), and epigenomic editing based on CRISPR-Cas9, gives grounds for optimism in solving problems of introducing epigenetic phenomena in livestock breeding.     

Epigenetic mechanisms in drug addiction

Changes in gene expression in brain reward regions are thought to contribute to the pathogenesis and persistence of drug addiction. Recent studies have begun to focus on the molecular mechanisms by which drugs of abuse and related environmental stimuli, such as drug-associated cues or stress, converge on the genome to alter specific gene programs. Increasing evidence suggests that these stable gene expression changes in neurons are mediated in part by epigenetic mechanisms that alter chromatin structure on specific gene promoters. This review discusses recent findings from behavioral, molecular and bioinformatic approaches being used to understand the complex epigenetic regulation of gene expression by drugs of abuse. This novel mechanistic insight might open new avenues for improved treatments of drug addiction.     

Epigenetic events in malignant melanoma

Irreversible changes in the DNA sequence, including chromosomal deletions or amplification, activating or inactivating mutations in genes, have been implicated in the development and progression of melanoma. However, increasing attention is being turned towards the participation of 'epigenetic' events in melanoma progression that do not affect DNA sequence, but which nevertheless may lead to stable inherited changes in gene expression. Epigenetic events including histone modifications and DNA methylation play a key role in normal development and are crucial to establishing the correct program of gene expression. In contrast, mistargeting of such epigenetic modifications can lead to aberrant patterns of gene expression and loss of anti-cancer checkpoints. Thus, to date at least 50 genes have been reported to be dysregulated in melanoma by aberrant DNA methylation and accumulating evidence also suggests that mistargetting of histone modifications and altered chromatin remodeling activities will play a key role in melanoma. This review gives an overview of the many different types of epigenetic modifications and their involvement in cancer and especially in melanoma development and progression.     

DNA羟甲基化与表观遗传学调控

表观遗传学中的DNA甲基化与疾病的发生发展密不可分. DNA甲基化中的5-甲基胞嘧啶易发生氧化形成5 羟甲基胞嘧啶.此过程又称为羟甲基化修饰,已成为表观遗传学研究的一种新热点.羟甲基化与10-11易位家族蛋白（ten-eleven translocation,TET）的作用密切相关,它参与了基因的表达调控以及DNA去甲基化过程. 最近的羟甲基化研究主要集中在癌症和精神性疾病.针对日趋增多的相关研究,本文对DNA羟甲基化进行了全景式综述.     

Epigenetic inheritance in rice plants

BACKGROUND AND AIMS: Epigenetics is defined as mechanisms that regulate gene expression without base sequence alteration. One molecular basis is considered to be DNA cytosine methylation, which reversibly modifies DNA or chromatin structures. Although its correlation with epigenetic inheritance over generations has been circumstantially shown, evidence at the gene level has been limited. The present study aims to find genes whose methylation status directly correlates with inheritance of phenotypic changes. METHODS: DNA methylation in vivo was artificially reduced by treating rice (Oryza sativa ssp. japonica) seeds with 5-azadeoxycytidine, and the progeny were cultivated in the field for > 10 years. Genomic regions with changed methylation status were screened by the methylation-sensitive amplified polymorphysm (MSAP) method, and cytosine methylation was directly scanned by the bisulfite mapping method. Pathogen infection with Xanthomonas oryzae pv. oryzae, race PR2 was performed by the scissors-dip method on mature leaf blades. KEY RESULTS: The majority of seedlings were lethal, but some survived to maturity. One line designated as Line-2 showed a clear marker phenotype of dwarfism, which was stably inherited by the progeny over nine generations. MSAP screening identified six fragments, among which two were further characterized by DNA blot hybridization and direct methylation mapping. One clone encoding a retrotransposon gag-pol polyprotein showed a complete erasure of 5-methylcytosines in Line-2, but neither translocation nor expression of this region was detectable. The other clone encoded an Xa21-like protein, Xa21G. In wild-type plants, all cytosines were methylated within the promoter region, whereas in Line-2, corresponding methylation was completely erased throughout generations. Expression of Xa21G was not detectable in wild type but was constitutive in Line-2. When infected with X. oryzae pv. oryzae, against which Xa21 confers resistance in a gene-for-gene manner, the progeny of Line-2 were apparently resistant while the wild type was highly susceptible without Xa21G expression. CONCLUSIONS: These results indicated that demethylation was selective in Line-2, and that promoter demethylation abolished the constitutive silencing of Xa21G due to hypermethylation, resulting in acquisition of disease resistance. Both hypomethylation and resistant trait were stably inherited. This is a clear example of epigenetic inheritance, and supports the idea of Lamarckian inheritance which suggested acquired traits to be heritable.