Genomic imprinting in mammals: its life cycle, molecular mechanisms and reprogramming

Genomic imprinting, an epigenetic gene-marking phenomenon that occurs in the germline, leads to parental-origin-specific expression of a small subset of genes in mammals. Imprinting has a great impact on normal mammalian development, fetal growth, metabolism and adult behavior. The epigenetic imprints regarding the parental origin are established during male and female gametogenesis, passed to the zygote through fertilization, maintained throughout development and adult life, and erased in primordial germ cells before the new imprints are set. In this review, we focus on the recent discoveries on the mechanisms involved in the reprogramming and maintenance of the imprints. We also discuss the epigenetic changes that occur at imprinted loci in induced pluripotent stem cells.     

基因组印记与疾病研究进展

基因组印记是一种特别的非孟德尔遗传现象,即来自双亲的等位基因在子代中的差异性表达,是遗传后的基因调控方式,主要与基因组甲基化模式有关,包括去甲基化、重新甲基化及甲基化维持三个过程。印记基因主要通过对启动子、边界元件及非编码RNA的作用来调控基因表达。基因组印记异常与一些先天性疾病相关,也与肿瘤发生和易感性有关,     

Genomic imprinting and evolution of insect societies

Reproductive division of labor is a hallmark of social insect societies where individuals follow different developmental pathways resulting in distinct morphological castes. There has been a long controversy over the factors determining caste fate of individuals in social insects. Increasing evidence in the last two decades for heritable influences on division of labor put an end to the assumption that social insect broods are fully totipotent and environmental factors alone determine castes. Nevertheless, the genes that underlie hereditary effects on division of labor have not been identified in any social insects. Studies investigating the hereditary effects on caste determination might have overlooked non-genetic inheritance, while transmission to offspring of factors other than DNA sequences including epigenetic states can also affect offspring phenotype. Genomic imprinting is one of the most informative paradigms for understanding the consequences of interactions between the genome and the epigenome. Recent studies of genomic imprinting show that genes can be differentially marked in egg and sperm and inheritance of these epigenetic marks cause genes to be expressed in a parental-origin-specific manner in the offspring. By reviewing both the eusocial Hymenoptera and termites, I highlight the current theoretical and empirical evidence for genomic imprinting in eusocial insects and discuss how genomic imprinting acts in caste determination and social behavior and challenges for future studies. I also introduce the new idea that genomic imprinting plays an essential role in the origin of eusociality.     

Genomic imprinting in plants: observations and evolutionary implications

The epigenetic phenomenon of genomic imprinting occurs among both plants and animals. In species where imprinting is observed, there are parent-of-origin effects on the expression of imprinted genes in offspring. This review focuses on imprinting in plants with examples from maize, where gene imprinting was first described, and Arabidopsis. Our current understanding of imprinting in plants is presented in the context of cytosine methylation and imprinting in mammals, where developmentally essential genes are imprinted. Important considerations include the structure and organization of imprinted genes and the role of regional, differential methylation. Imprinting in plants may be related to other epigenetic phenomena including paramutation and transgene silencing. Finally, we discuss the role of gene structure and evolutionary implications of imprinting in plants.     

Genomic imprinting and human hereditary disorders

Modern data are reviewed that concern hereditary disorders caused by abnormal expression of imprinted genes rather than mutations and structural aberrations. As an example, the molecular organization of the critical chromosomal region 15(q11.2–q13) and the possible pathogenetic mechanisms are described in detail for Prader-Willi and Angelman syndromes.     

Genomic imprinting of chromatin inDrosophila melanogaster

During gametogenesis, chromosomes may become imprinted with information which facilitates proper expression of the DNA in offspring. We have used a position effect variegation mutant as a reporter system to investigate the possibility of imprinting inDrosophila melanogaster. Genetic crosses were performed in which the variegating gene and a strong modifier of variegation were present either within the same parental genome or in opposite parental genomes in all possible combinations. Our results indicate that the presence of the variegating chromosome and a modifier chromosome in the same parental genome can alter the amount of variegation formed in progeny. The genomic imprinting we observed is not determined by the parental origin of the variegating chromosome but is instead determined by the genetic background the variegating chromosome is subjected to during gametogenesis.     

植物多倍体中的基因组印记

植物多倍体在自然界中广泛存在,这说明拥有多套遗传物质使得多倍体的适应进化具有优势。新多倍体形成后,一些基因组范围的变化较迅速地发生在多倍体形成开端,另一些在长期进化中发生。由于受到遗传、表观等因素的影响,亲本对于新形成多倍体基因组的贡献不均衡。这种偏向于某个亲本基因组的显性优势,称为基因组印记。植物多倍体中的基因组印记表现为基因组偏向性的序列消除、不均衡基因表达、基因沉默,这些受到基因组合并及DNA甲基化、核仁显性等表观因素影响。本文旨在为多倍体基因组进化及育种的相关研究提供参考。     

Genomic imprinting in the development and evolution of psychotic spectrum conditions

I review and evaluate genetic and genomic evidence salient to the hypothesis that the development and evolution of psychotic spectrum conditions have been mediated in part by alterations of imprinted genes expressed in the brain. Evidence from the genetics and genomics of schizophrenia, bipolar disorder, major depression, Prader‐Willi syndrome, Klinefelter syndrome, and other neurogenetic conditions support the hypothesis that the etiologies of psychotic spectrum conditions commonly involve genetic and epigenetic imbalances in the effects of imprinted genes, with a bias towards increased relative effects from imprinted genes with maternal expression or other genes favouring maternal interests. By contrast, autistic spectrum conditions, including Kanner autism, Asperger syndrome, Rett syndrome, Turner syndrome, Angelman syndrome, and Beckwith‐Wiedemann syndrome, commonly engender increased relative effects from paternally expressed imprinted genes, or reduced effects from genes favouring maternal interests. Imprinted‐gene effects on the etiologies of autistic and psychotic spectrum conditions parallel the diametric effects of imprinted genes in placental and foetal development, in that psychotic spectrum conditions tend to be associated with undergrowth and relatively‐slow brain development, whereas some autistic spectrum conditions involve brain and body overgrowth, especially in foetal development and early childhood. An important role for imprinted genes in the etiologies of psychotic and autistic spectrum conditions is consistent with neurodevelopmental models of these disorders, and with predictions from the conflict theory of genomic imprinting.     

Competitive signal discrimination, methylation reprogramming and genomic imprinting

Genomic imprinting (parent-of-origin-dependent gene regulation) is associated with intra-genomic evolutionary conflict over the optimal pattern of gene expression. Most theoretical models of imprinting focus on the conflict between the maternally and paternally derived alleles at an imprinted locus. Recently, however, more attention has been focused on multi-directional conflicts involving not only the imprinted gene itself, but also the genes that encode the regulatory machinery responsible for establishing and maintaining imprinted gene expression. In this paper, I examine the conflict involved in epigenetic reprogramming of imprinted genes in early mammalian embryonic development. In the earliest phase of development, maternal-store proteins are responsible for most regulatory activity in the embryo. These proteins are under selection to maximize the mother's inclusive fitness, which is not identical to that of either of the sets of genes present in the embryo. Both the maternally and paternally derived genomes in the embryo favor maintenance of the epigenetic modifications established in the female and male germlines, respectively. Maternal-store proteins favor maintenance of some of these modifications, but erasure of others. Here I consider the logical structure of the machinery responsible for these two activities. Methylation maintenance is most effectively performed by AND-linked architectures, which may explain the unusual trafficking behavior of the oocyte-specific DNA methyltransferase, Dnmt1o. By contrast, demethylation is better supported by OR-linked architectures, which may explain the difficulty in identifying the factor(s) responsible for the active demethylation of the paternal genome following fertilization.     

Genomic imprinting in mammals-epigenetic parental memories

Genomic imprinting is an epigenetic phenomenon that brings the difference of expression between paternally or maternally derived alleles and is specific for mammals in vertebrates. This imprint is established in the parental germlines and then inherited to the next generation to regulate expression of imprinted genes that are essential to support proper embryonic development. More than one hundred imprinted genes have been identified in mice and humans. Some are essential for embryonic development, especially placental formation, and others regulate metabolism, behavior and physiological functions. In humans, disruption of genomic imprinting causes several diseases, including cancer. Recently, the molecular mechanisms of genomic imprinting are getting clarified. How do parents regulate gene expression of their children? Why and how is genomic imprinting evolved in mammals? The review offers a handful of recent progress in this area.     

后生遗传修饰及其对动物克隆的影响

近年来,不断有新的哺乳动物和两栖类动物被成功克隆,但这并不能掩盖克隆效率过低和克隆动物异常的现实,为了解决这一问题,人们对克隆机理进行了大量研究。高度分化的体细胞核在去核的卵质中去分化和再程序化不完全是导致动物克隆失败的主要原因,而去分化和再程序化不完全主要是由于基因组去甲基化不充分和过早再甲基化引起克隆胚中甲基化水平比正常胚中偏高所至,这可引起一些重要基因的异常表达,尤其是印记基因。这些机制的研究对提高克隆效率有着重要意义。     

Genomic imprinting in plants

Genomic imprinting attracted particular attention in the 1980’s following the discovery that the parental origin of genetic information is essential for normal development of eutherians,1,2 for review see.3 The term imprinting was first introduced in the 1960s to describe the elimination of the paternal chromosomes during spermatogenesis in the Sciarid fly.4?6Today the term genomic imprinting mainly refers to parent?of?origin specific effects distinguishing each parental genome which can be regarded as memories, or “imprints”.7,8 Breaking the rules of Mendel, genomic imprinting is an epigenetic phenomenon per se. Epigenetics is currently defined as the study of mitotically or meiotically heritable changes in gene expression without any change in DNA sequence9,10 and it is intimately linked to the study of inheritance of chromatin states.11 Gene imprinting currently refers to differential expression of autosomal genes according to their parent of origin.12The phenomenon of genomic imprinting explains several cases of parent?specific human disorders.13 To date over 80 imprinted genes have been described in mammals14 and their parent?of?origin specific expression can correlate with changes in DNA methylation patterns, antisense noncoding RNAs and chromatin folding.3 Epigenetic imprints can either activate or silence the “imprinted” allele, and hence imprinting can be associated with either an expressed or silenced allele.15 In mammals, the number of paternally expressed imprinted genes is almost equivalent to the number of maternally expressed genes and the imprinted status can differs according to tissue, developmental stage and species. It is then crucial for our understanding to clearly indicate the status of imprinting (i.e., paternally or maternally expressed) and the context (e.g., species, developmental stage, tissue).     

生殖细胞及早期胚胎基因组印记的表观调控

基因组印记是一种区别父母等位基因的表观遗传过程,可导致父源和母源基因特异性表达。印记是在配子发生过程中全基因组表观重编程时获得的,且在早期胚胎发育过程中得以维持。因此,在全基因组重编程过程中,对印记的识别和维持十分重要。本文概述了原始生殖细胞的印记清除、双亲原始生殖细胞的印记获得以及早期胚胎发育过程中印记维持的相关过程,并对在印记区域内保护印记基因免受全基因组DNA去甲基化的表观遗传因子的相关作用机制进行了讨论。     

Small regulatory RNAs controlled by genomic imprinting and their contribution to human disease

More than a hundred protein-coding genes are controlled by genomic imprinting in humans. These atypical genes are organized in chromosomal domains, each of which is controlled by a differentially methylated "imprinting control region" (ICR). How ICRs mediate the parental allele-specific expression of close-by genes is now becoming understood. At several imprinted domains, this epigenetic mechanism involves the action of long non-coding RNAs. It is less well appreciated that imprinted gene domains also transcribe hundreds of microRNA and small nucleolar RNA genes and that these represent the densest clusters of small RNA genes in mammalian genomes. The evolutionary reasons for this remarkable enrichment of small regulatory RNAs at imprinted domains remain unclear. However, recent studies show that imprinted small RNAs modulate specific functions in development and metabolism and also are frequently perturbed in cancer. Here, we review our current understanding of imprinted small RNAs in the human genome and discuss how perturbation of their expression contributes to disease.     

Insights into epigenetic patterns in mammalian early embryos

Mammalian fertilization begins with the fusion of two specialized gametes,followed by major epigenetic remodeling leading to the formation of a totipotent embryo.During the development of the pre-implantation embryo,precise reprogramming progress is a prerequisite for avoiding developmental defects or embryonic lethality,but the underlying molecular mechanisms remain elusive.For the past few years,unprecedented breakthroughs have been made in mapping the regulatory network of dynamic epigenomes during mammalian early embryo development,taking advantage of multiple advances and innovations in low-input genome-wide chromatin analysis technologies.The aim of this review is to highlight the most recent progress in understanding the mechanisms of epigenetic remodeling during early embryogenesis in mammals,including DNA methylation,histone modifications,chromatin accessibility and 3D chromatin organization.