Genetic and epigenetic markers of gliomas

Malignant gliomas are aggressive and highly invasive tumors. Various genetic and epigenetic changes are common for these tumors. Mostly they concern the genes involved in cell-cycle regulation, apoptotic pathways, cell invasion, angiogenesis, and cell metabolism. The role of epigenetic mechanisms in glioma malignant transformation, despite recent progress, is uncertain and remains under intense study. This review describes the mechanisms of epigenetic regulation of gene expression, including posttranslational modifications of histones, DNA methylation in promoter regions, and microRNA regulation. The genetic and epigenetic factors driving the pathogenesis of gliomas in their possible mutual influence and the potential epigenetic targets that can be used for diagnostics and new therapeutic approaches are also discussed.     

Epigenetics and cell cycle regulation in cystogenesis

The role of genetic mutations in the development of polycystic kidney disease (PKD), such as alterations in PKD1 and PKD2 genes in autosomal dominant PKD (ADPKD), is well understood. However, the significance of epigenetic mechanisms in the progression of PKD remains unclear and is increasingly being investigated. The term of epigenetics describes a range of mechanisms in genome function that do not solely result from the DNA sequence itself. Epigenetic information can be inherited during mammalian cell division to sustain phenotype specifically and physiologically responsive gene expression in the progeny cells. A multitude of functional studies of epigenetic modifiers and systematic genome-wide mapping of epigenetic marks reveal the importance of epigenomic mechanisms, including DNA methylation, histone/chromatin modifications and non-coding RNAs, in PKD pathologies. Deregulated proliferation is a characteristic feature of cystic renal epithelial cells. Moreover, defects in many of the molecules that regulate the cell cycle have been implicated in cyst formation and progression. Recent evidence suggests that alterations of DNA methylation and histone modifications on specific genes and the whole genome involved in cell cycle regulation and contribute to the pathogenesis of PKD. This review summarizes the recent advances of epigenetic mechanisms in PKD, which helps us to define the term of “PKD epigenetics” and group PKD epigenetic changes in three categories. In particularly, this review focuses on the interplay of epigenetic mechanisms with cell cycle regulation during normal cell cycle progression and cystic cell proliferation, and discusses the potential to detect and quantify DNA methylation from body fluids as diagnostic/prognostic biomarkers. Collectively, this review provides concepts and examples of epigenetics in cell cycle regulation to reveal a broad view of different aspects of epigenetics in biology and PKD, which may facilitate to identify possible novel therapeutic intervention points and to explore epigenetic biomarkers in PKD.     

Epigenetic regulation in human melanoma: past and future

The development and progression of melanoma have been attributed to independent or combined genetic and epigenetic events. There has been remarkable progress in understanding melanoma pathogenesis in terms of genetic alterations. However, recent studies have revealed a complex involvement of epigenetic mechanisms in the regulation of gene expression, including methylation, chromatin modification and remodeling, and the diverse activities of non-coding RNAs. The roles of gene methylation and miRNAs have been relatively well studied in melanoma, but other studies have shown that changes in chromatin status and in the differential expression of long non-coding RNAs can lead to altered regulation of key genes. Taken together, they affect the functioning of signaling pathways that influence each other, intersect, and form networks in which local perturbations disturb the activity of the whole system. Here, we focus on how epigenetic events intertwine with these pathways and contribute to the molecular pathogenesis of melanoma.     

Epigenetic regulation of germ cell differentiation

Germ cells and somatic cells have the identical genome. However, unlike the mortal fate of somatic cells, germ cells have the unique ability to differentiate into gametes that retain totipotency and produce an entire organism upon fertilization. The processes by which germ cells differentiate into gametes, and those by which gametes become embryos, involve dramatic cellular differentiation accompanied by drastic changes in gene expression, which are tightly regulated by genetic circuitries as well as epigenetic mechanisms. Epigenetic regulation refers to heritable changes in gene expression that are not due to changes in primary DNA sequence. The past decade has witnessed an ever-increasing understanding of epigenetic regulation in many different cell types/tissues during embryonic development and adult homeostasis. In this review, we focus on recent discoveries of epigenetic regulation of germ cell differentiation in various metazoan model organisms, including worms, flies, and mammals.     

Regulation of cellular chromatin state

The identity and functionality of eukaryotic cells is defined not just by their genomic sequence which remains constant between cell types, but by their gene expression profiles governed by epigenetic mechanisms. Epigenetic controls maintain and change the chromatin state throughout development, as exemplified by the setting up of cellular memory for the regulation and maintenance of homeotic genes in proliferating progenitors during embryonic development. Higher order chromatin structure in reversibly arrested adult stem cells also involves epigenetic regulation and in this review we highlight common trends governing chromatin states, focusing on quiescence and differentiation during myogenesis. Together, these diverse developmental modules reveal the dynamic nature of chromatin regulation providing fresh insights into the role of epigenetic mechanisms in potentiating development and differentiation.     

表遗传学与肿瘤

表遗传学通过对核小体上D NA和组蛋白的结构修饰以及其后导致的染色质结构改变而对局部或整体的基因表达产生重要的调控作用.肿瘤分子生物学研究表明,表遗传学的紊乱与基因的变异一起参与了包括肿瘤细胞生长和分化、细胞周期的调控、D N A修复与重新表达、原癌基因的激活、肿瘤细胞的转移及肿瘤细胞逃避宿主免疫监视等肿瘤发生发展的整个过程.相对于基因变异而言,可逆的表遗传学调控为肿瘤的治疗提供一个全新的方向,而对其分子机制的研究为抗肿瘤药物的设计也提供了一个全新的靶点,从而对肿瘤的临床治疗具有重要的意义.     

GENETIC VARIATION AND THE EVOLUTION OF EPIGENETIC REGULATION

Epigenetic variation has been observed in a range of organisms, leading to questions of the adaptive significance of this variation. In this study, we present a model to explore the ecological and genetic conditions that select for epigenetic regulation. We find that the rate of temporal environmental change is a key factor controlling the features of this evolution. When the environment fluctuates rapidly between states with different phenotypic optima, epigenetic regulation may evolve but we expect to observe low transgenerational inheritance of epigenetic states, whereas when this fluctuation occurs over longer time scales, regulation may evolve to generate epigenetic states that are inherited faithfully for many generations. In all cases, the underlying genetic variation at the epigenetically regulated locus is a crucial factor determining the range of conditions that allow for evolution of epigenetic mechanisms.     

Current advances in epigenetic modification and alteration during mammalian ovarian folliculogenesis

During the growth and development of mammalian ovarian follicles, the activation and deactivation of mass genes are under the synergistic control of diverse modifiers through genetic and epigenetic events. Many factors regulate gene activity and functions through epigenetic modification without altering the DNA sequence, and the common mechanisms may include but are not limited to: DNA methylation, histone modifications (e.g., acetylation, deacetylation, phosphorylation, methylation, and ubiquitination), and RNA-associated silencing of gene expression by noncoding RNA. Over the past decade, substantial progress has been achieved in studies involving the epigenetic alterations during mammalian germ cell development. A number of candidate regulatory factors have been identified. This review focuses on the current available information of epigenetic alterations (e.g., DNA methylation, histone modification, noncoding-RNA-mediated regulation) during mammalian folliculogenesis and recounts when and how epigenetic patterns are differentially established, maintained, or altered in this process. Based on different types of epigenetic regulation, our review follows the temporal progression of events during ovarian folliculogenesis and describes the epigenetic changes and their contributions to germ cell-specific functions at each stage (i.e., primordial folliculogenesis (follicle formation), follicle maturation, and follicular atresia).     

Epigenetic gene regulation in stem cells and correlation to cancer

Through the classic study of genetics, much has been learned about the regulation and progression of human disease. Specifically, cancer has been defined as a disease driven by genetic alterations, including mutations in tumor-suppressor genes and oncogenes, as well as chromosomal abnormalities. However, the study of normal human development has identified that in addition to classical genetics, regulation of gene expression is also modified by ‘epigenetic’ alterations including chromatin remodeling and histone variants, DNA methylation, the regulation of polycomb group proteins, and the epigenetic function of non-coding RNA. These changes are modifications inherited during both meiosis and mitosis, yet they do not result in alterations of the actual DNA sequence. A number of biological questions are directly influenced by epigenetics, such as how does a cell know when to divide, differentiate or remain quiescent, and more importantly, what happens when these pathways become altered? Do these alterations lead to the development and/or progression of cancer? This review will focus on summarizing the limited current literature involving epigenetic alterations in the context of human cancer stems cells (CSCs). The extent to which epigenetic changes define cell fate, identity, and phenotype are still under intense investigation, and many questions remain largely unanswered. Before discussing epigenetic gene silencing in CSCs, the different classifications of stem cells and their properties will be introduced. This will be followed by an introduction to the different epigenetic mechanisms. Finally, there will be a discussion of the current knowledge of epigenetic modifications in stem cells, specifically what is known from rodent systems and established cancer cell lines, and how they are leading us to understand human stem cells.     

The epigenetics of CHARGE syndrome

In biology, we continue to appreciate the fact that the DNA sequence alone falls short when attempting to explain the intricate inheritance patterns for complex traits. This is particularly true for human disorders that appear to have simple genetic causes. The study of epigenetics, and the increased access to the epigenetic profiles of different tissues has begun to shed light on the genetic complexity of many basic biological processes, both physiological and pathological. Epigenetics refers to heritable changes in gene expression that are not due to alterations in the DNA sequence. Various mechanisms of epigenetic regulation exist, including DNA methylation and histone modification. The identification, and increased understanding of key players and mechanisms of epigenetic regulation have begun to provide significant insight into the underlying origins of various human genetic disorders. One such disorder is CHARGE syndrome (OMIM #214800), which is a leading cause of deaf-blindness worldwide. A majority of CHARGE syndrome cases are caused by haploinsufficiency for the CHD7 gene, which encodes an ATP-dependent chromatin remodeling protein involved in the epigenetic regulation of gene expression. The CHD7 protein has been highly conserved throughout evolution, and research into the function of CHD7 homologs in multiple model systems has increased our understanding of this family of proteins, and epigenetic mechanisms in general. Here we provide a review of CHARGE syndrome, and discuss the epigenetic functions of CHD7 in humans and CHD7 homologs in model organisms.     

Allele-specific gene expression and epigenetic modifications and their application to understanding inheritance and cancer

Epigenetic information is characterized by its plasticity during development and differentiation as well as its stable transmission during mitotic cell divisions in somatic tissues. This duality contrasts to genetic information, which is essentially static and identical in every cell in an organism with only a few exceptions such as immunoglobulin genes in lymphocytes. Epigenetics is traditionally perceived as a means to regulate gene expression without a change in DNA sequence. This, however, does not exclude a potential role for genetic variations in providing differential backgrounds on which epigenetic modulations and their regulatory consequences are achieved. An effective approach to investigating the interplay between genetic variations and epigenetic variations is through allele-specific analysis of epigenetics and gene expression. Such studies have generated many new insights into functions of genetic variations, mechanisms of gene expression regulation, and the role of mutations and epigenetic alterations in human cancer. This article is part of a Special Issue entitled: Chromatin in time and space.     

Biological pathways to adaptability--interactions between genome, epigenome, nervous system and environment for adaptive behavior

Because living systems depend on their environment, the evolution of environmental adaptability is inseparable from the evolution of life itself (Pross 2003). In animals and humans, environmental adaptability extends further to adaptive behavior. It has recently emerged that individual adaptability depends on the interaction of adaptation mechanisms at diverse functional levels. This interaction enables the integration of genetic, epigenetic and environmental factors for coordinated regulation of adaptations. In this review, we first present the basis for the regulation of adaptation mechanisms across functional levels. We then focus on neuronal activity-regulated adaptation mechanisms that involve the regulation of genes, noncoding DNA (ncDNA), ncRNAs and proteins to change the structural and functional properties of neurons. Finally, we discuss a selection of these important neuronal activity-regulated molecules and their effects on brain structure and function and on behavior. Most of the evidence so far is based on sampling of animal tissue or post-mortem studies in humans. However, we also present techniques that combine genetic with behavioral and neurophysiological measures in humans (e.g. genetic imaging) and discuss their potential and limitations. We argue that we need to understand how neuronal activity-dependent adaptation mechanisms integrate genetic, epigenetic and experience-dependent signals in order to explain individual variations in behavior and cognitive performance.