Imprinting centers, chromatin structure, and disease

Two regions that best exemplify the role of genetic imprinting in human disease are the Prader-Willi syndrome/Angelman syndrome (PWS/AS) region in 15q11-q13 and the Beckwith-Wiedemann syndrome (BWS) region in 11p15.5. In both regions, cis-acting sequences known as imprinting centers (ICs) regulate parent-specific gene expression bidirectionally over long distances. ICs for both regions are subject to parent-specific epigenetic marking by covalent modification of DNA and histones. In this review, we summarize our current understanding of IC function and IC modification in these two regions.     

Geomagnetic Reversals and Genome Imprinting

If it is more fundamental to formulate biological expression in terms of electromagnetic fields, does this also imply that living things are especially sensitive to the external electromagnetic environment? Specifically, we examine possible genomic effects due to reversals of the geomagnetic field. To maintain sensitivity following a reversal, the Wiltschko hypothesis for the avian magnetic compass can be subsumed under an NB imprinting paradigm, where N is the horizontal vector pointing to magnetic north and B the geomagnetic field vector. Even with a compass that is invariant under reversals, there are nevertheless potential difficulties due to discontinuities in the magnitude of the field during the transition between one chron and the next. Indeed, transitions may be one reason for other-than-magnetic avian auxiliary compasses. Additional problems may also arise during transitions because of high rates of change in B. However, the largest reported dB/dt (Steens Mountain event) is estimated at 1 /u.T/day, seemingly too small to induce significant Faraday current density. Reversals may have also helped determine the nature of the interaction mechanism between GMF and living systems. Mechanisms based on fixed magnetic moments may not be capable of adapting to the reversal process. A better case can be made for an ion cyclotron resonance interaction. Direct involvement in the cell-signaling activities of biological ions would provide such flexibility, and also point to a broader role for the GMF in modulating CNS function than merely to provide orientation.     

Imprinting evolution and human health

Genomic imprinting results in parent-of-origin-dependent, monoallelic expression of genes. The functional haploid state of these genes has far-reaching consequences. Not only has imprinting been implicated in accelerating mammalian speciation, there is growing evidence that it is also involved in the pathogenesis of several human conditions, particularly cancer and neurological disorders. Epigenetic regulatory mechanisms govern the parental allele-specific silencing of imprinted genes, and many theories have attempted to explain the driving force for the evolution of this unique form of gene control. This review discusses the evolution of imprinting in Therian mammals, and the importance of imprinted genes in human health and disease.     

Imprinting in plants

This review discusses the modern issues in epigenetic regulation in plants related to the imprinting at the levels of genome, locus, and gene. The data described follow the historical order: from the beginning of research into non-crossability of plant forms with different ploidies to the recent communications about allelic imprinting at r1 locus of maize and the control of synthesis of storage proteins with a high forage value. The classical experiments of Kermicle and Lin on the cytogenetic confirmation of the role of parental genome ratio in the endosperm in a successful development of viable caryopses are described in detail. Uniqueness of the experimental technique used by these authors is emphasized. The variants for overcoming the effect of imprinted signal in apomicts and plants with a tetrasporic embryo sac are considered. A considerable attention is paid to the imprinting in the species with polyploid series and to the hypothesis of endosperm balance number. The issues of potential practical application of imprinting in breeding practice are discussed. The results obtained in this direction demonstrate the ways to increase the forage value of maize zeins.     

基因组印迹与种子发育

胚乳介导营养物质从母体到胚的转运过程,是开花植物中发生印迹的重要部位。胚乳的发育异常会导致胚的败育。在拟南芥中已鉴定到三个FIS (fertilization-independent seed) 基因,能制止无需受精即形成种子的发育过程,即FIS1/ MEDEA、FIS2和FIS3/FIE。其中MEDEA基因是胚乳发育的主要调控基因,在胚乳中被印迹。FWA基因也在胚乳中被印迹。系统阐述了植物基因组印迹的机理以及MEA和FWA印迹机制的研究进展,并介绍了印迹发生的亲本冲突学说、印迹的方式及其它已报道的印迹基因。     

Imprinting in neurons

Although most imprinted genes display parent-origin-specific gene expression in tissues where they are transcribed, some genes are imprinted in a tissue-specific manner. Genes that show brain-specific imprinting or brain-specific lack of imprinting present a unique opportunity to study the process of imprinting during tissue differentiation. In this review, I introduce the systematic study of brain-cell-lineage-specific imprinting using a primary brain cell culture system, where neurons or glial cells are cultured separately. Two reports using the primary brain cell culture revealed brain-cell-lineage-specific imprinting in Ube3a and Igf2r, which had previously been described to show brain-specific imprinting and brain-specific lack of imprinting, respectively. Such brain-cell-lineage-specific imprinting was associated with cell-specific epigenetic modifications, especially with their reciprocally imprinted antisense non-coding RNAs, Ube3a-ATS and Air. These results emphasize the necessity of imprinting analysis at the cell level rather than in whole brain tissue during brain differentiation. The brain cell culture system provides us with a new powerful tool to understand the molecular mechanism of brain-specific imprinting.     

Imprinting errors and developmental asymmetry

There are, in the broadest sense, two mechanisms by which gene expression can be extinguished in vertebrates. The first of these is based on mass action effects of positive and negative regulatory factors and is termed activation and repression; the second is independent of positive regulatory factors but is based on the history of the affected gene and is termed silencing. It can be said, again in the broadest sense, that imprinted genes, genes subject to X inactivation, and transposon promoters are subject to silencing, while the promoters of tissue-specific genes in non-expressing tissues are controlled by activation and repression. The escape of imprinted genes from silencing through unknown mechanisms can cause developmental abnormalities and can predispose to the formation of embryonal tumours. One developmental disorder caused by loss of imprinting of genes on chromosome 11p15.5 is Beckwith-Wiedemann syndrome (BWS). This syndrome has long been known to be inexplicably common in monozygotic twins; the twins are nearly always discordant for BWS, and nearly all twins are female. A loss of imprinting model based on stochastic errors in the nucleocytoplasmic trafficking of the DNA methyltransferase DNMT1, or a paternally expressed function that opposes maintenance methylation of maternally repressed growth-enhancing genes, is proposed to explain the perplexing genetics of BWS in monozygotic twins.     

Imprinting in plants

This review discusses the modern issues in epigenetic regulation in plants related to the imprinting at the levels of genome, locus, and gene. The data described follow the historical order: from the beginning of research into non-crossability of plant forms with different ploidies to the recent communications about allelic imprinting at r1 locus of maize and the control of synthesis of storage proteins with a high forage value. The classical experiments of Kermicle and Lin on the cytogenetic confirmation of the role of parental genome ratio in the endosperm in a successful development of viable caryopses are described in detail. Uniqueness of the experimental technique used by these authors is emphasized. The variants for overcoming the effect of imprinted signal in apomicts and plants with a tetrasporic embryo sac are considered. A considerable attention is paid to the imprinting in the species with polyploid series and to the hypothesis of endosperm balance number. The issues of potential practical application of imprinting in breeding practice are discussed. The results obtained in this direction demonstrate the ways to increase the forage value of maize zeins.     

基因组印迹调节

虽然大多数哺乳动物基因都是双座位表达,但是有一少部分基因发生印迹,只有父母双方基因中的一个实际表达,这种表观遗传过程迁涉到发育不同阶段基因的表达调节,十分复杂,原则上印迹基因在生殖细胞中必须用表观遗传标记顺式标记,这些标记能够通过细胞分裂进行保存,在成熟生物分化细胞中能够指导多基因单座位表达,在生殖细胞形成早期两个座位上的表达差别必须消除,以便在成熟生殖细胞中重新设置印迹,在该文中,概述了目前所知介导这些过程的分子机制。     

Genomic Imprinting in Mammals

Genomic imprinting affects a subset of genes in mammals and results in a monoallelic, parental-specific expression pattern. Most of these genes are located in clusters that are regulated through the use of insulators or long noncoding RNAs (lncRNAs). To distinguish the parental alleles, imprinted genes are epigenetically marked in gametes at imprinting control elements through the use of DNA methylation at the very least. Imprinted gene expression is subsequently conferred through lncRNAs, histone modifications, insulators, and higher-order chromatin structure. Such imprints are maintained after fertilization through these mechanisms despite extensive reprogramming of the mammalian genome. Genomic imprinting is an excellent model for understanding mammalian epigenetic regulation.     

基因组印迹的起动与沉默

在配子中基因组印迹起动复合物的结合引发印迹现象,印迹起动复合物中有多种可鉴定成分,存在结合的精确时间和机制,印迹起动复合物似乎仅出现在生殖细胞系,而甲基CpG结合蛋白则能延续增殖印迹,因此基因组印迹调节着发育基因或组织特异性单等位基因的瞬时表达及大染色体结构域中基因之间的相互作用 。     

Parental Imprinting in Drosophila

Genetic imprinting is a form of epigenetic silencing. But with a twist. The twist is that while imprinting results in the silencing of genes, chromosome regions or entire chromosome sets, this silencing occurs only after transmission of the imprinted region by one sex of parent. Thus genetic imprinting reflects intertwined levels of epigenetic and developmental modulation of gene expression. Imprinting has been well documented and studied in Drosophila, however, these studies have remained largely unknown due to nothing more significant than differences in terminology. Imprinting in Drosophilais invariably associated with heterochromatin or regions with unusual chromatin structure. The imprint appears to spread from imprinted centers that reside within heterochromatin and these are, seemingly, the only regions that are normally imprinted in Drosophila. This is significant as it implies that while imprinting occurs in Drosophila, it is generally without phenotypic consequence. Hence the evolution of imprinting, at least in Drosophila, is unlikely to be driven by the function of specific imprinted genes. Thus, the study of imprinting in Drosophilahas the potential to illuminate the mechanism and biological function of imprinting, and challenge models based solely on imprinting of mammalian genes. This revised version was published online in July 2006 with corrections to the Cover Date.     

基因印记与lncRNA

基因印记是一种表观遗传调控机制,在二倍体哺乳动物的发育过程中,基因印记可以调控来自亲代的等位基因差异表达。非编码RNA是不编码蛋白质的RNA,它在RNA水平调控基因表达。研究表明大多数印记基因中存在长非编码RNA（长度>200nt的非编码RNA）的转录,长非编码RNA主要通过顺式的转录干扰作用来实现基因印记。同时基因印记及其相关的长非编码RNA异常表达与许多先天疾病相关,迄今已发现数十种人类遗传疾病与基因印记有关,而lncRNA引起的基因印记在疾病的发生和治疗中起着重要作用。