Genomic imprinting in mammals

A review of the data on the mechanisms and effects of genomic imprinting, an epigenetic phenomenon regulating the development in placentate mammals, is presented. In contrast to the majority of gene loci with biallelic expression, the expression of imprinted loci is monoallelic. In humans and mice, more than 300 imprinted loci have been identified, in which maternal or paternal alleles may either be expressed or be found in a repressed state during ontogeny. Imprinting is established during gametogenesis, and the repression of an allele of the imprinted locus is determined by methylation of the key regulatory element of this allele. Both the maternal and paternal chromosome sets are required for normal development in mammals. This is why parthenogenesis and androgenesis in these animals are impossible in nature. As a result of differential gene expression of many imprinted loci, the balance of gene activity is established, which is necessary for normal proliferation and differentiation of various cell clones in embryogenesis. Many human developmental abnormalities and syndromes are determined by defective genomic imprinting. In particular, the loss of imprints, which is followed by the occurrence of biallelic expression of some imprinted loci, may cause malignant tumors.     

Genomic imprinting in mammals

In contrast to the biallelic expression of most genes, expression of imprinted genes is monoallelic and depends on the sex of the transmitting parents. In humans it has been implicated in some developmental failures, neurodevelopmental and neurobehavioral disorders (such as Prader-Willi/Angelman, Silver-Russel or Beckwith-Wiedemann syndromes). The aim of this review is to present the phenomenon of parental imprinting as well as its molecular mechanism in various mammals. Several maternal and paternal imprinted genes and gene clusters are described.     

Genomic imprinting mechanisms in mammals

Genomic imprinting is a form of epigenetic gene regulation that results in expression from a single allele in a parent-of-origin-dependent manner. This form of monoallelic expression affects a small but growing number of genes and is essential to normal mammalian development. Despite extensive studies and some major breakthroughs regarding this intriguing phenomenon, we have not yet fully characterized the underlying molecular mechanisms of genomic imprinting. This is in part due to the complexity of the system in that the epigenetic markings required for proper imprinting must be established in the germline, maintained throughout development, and then erased before being re-established in the next generation's germline. Furthermore, imprinted gene expression is often tissue or stage-specific. It has also become clear that while imprinted loci across the genome seem to rely consistently on epigenetic markings of DNA methylation and/or histone modifications to discern parental alleles, the regulatory activities underlying these markings vary among loci. Here, we discuss different modes of imprinting regulation in mammals and how perturbations of these systems result in human disease. We focus on the mechanism of genomic imprinting mediated by insulators as is present at the H19/Igf2 locus, and by non-coding RNA present at the Igf2r and Kcnq1 loci. In addition to imprinting mechanisms at autosomal loci, what is known about imprinted X-chromosome inactivation and how it compares to autosomal imprinting is also discussed. Overall, this review summarizes many years of imprinting research, while pointing out exciting new discoveries that further elucidate the mechanism of genomic imprinting, and speculating on areas that require further investigation.     

Genomic imprinting and problem of parthenogenesis in mammals

Genomic imprinting belongs by its nature to problems of epigenetics, which studies hereditary changes in gene expression not related to defective sequences of DNA nucleotides. Epigenetic mechanisms of control, including genomic imprinting, are involved in many processes of normal and pathological development of humans and animals. Disturbances of genomic imprinting may lead to various consequences, such as formation of developmental anomalies and syndromes in humans, appearance of the large offspring syndrome and increased mortality upon cloning of mammals, and death of parthenogenetic embryos soon after implantation and beginning of organogenesis. The death of diploid parthenogenetic or androgenetic mammalian embryos is determined by the absence of expression of the genes of imprinted loci of the maternal or paternal genome, which leads to significant defects in development of tissues and organs. A review is provided of the studies aimed at search of possible normalization of misbalanced gene activity and modulation of genomic imprinting effects during parthenogenetic development in mammals.     

Genomic imprinting is a barrier to parthenogenesis in mammals

Only mammals have relinquished parthenogenesis as a means of producing descendants. Bi-parental reproduction is necessary due to parent-specific epigenetic modification of the genome during gametogenesis, which leads to non-equivalent expression of imprinted genes from the maternal and paternal alleles. However, a series of our work showed that alteration of maternal imprinting by oocyte reconstruction using non-growing oocytes, together with deletion of the H19 gene provide appropriate expression of imprinted genes from the maternal genome. The resulting ng (non-growing)/fg (fully-grown) parthenogenic embryos were developed to term. Here, we discuss how the parthenogenetic embryos survived as normal individuals.     

Genomic imprinting in plants and mammals: how life history constrains convergence

In both flowering plants and mammals, DNA methylation is involved in silencing alleles of imprinted genes, but surprising differences in imprinting control are emerging between the two taxa which may be traced to differences in their life cycles. Imprinted gene expression in plants occurs in the endosperm, a separate fertilisation product which transmits nutrients to the embryo and does not contribute a genome to the next generation. Regulation of expression of the known imprinted genes in Arabidopsis involves a cascade of gene expression beginning in the gametophyte, a haploid life phase interposed between the meiotic products and the gametes, which evolved from free-living organisms that constitute the dominant life phase of lower plants. Although the gametophytes of flowering plants are highly reduced they still express large numbers of genes, perhaps reflecting their evolutionary legacy, and which may now be recruited for control of imprinting. Strikingly, the genes at the top of the expression cascade appear to be specifically activated by demethylation, rather than targeted for silencing. Unlike in mammals, there is no evidence for global resetting of methylation in plants, and although imprinting involves the activity of a maintenance methyltransferase, de novo methyltransferases do not appear to be required. Plants do not set aside a germline; instead the cells that undergo meiosis to produce gametophytes differentiate in the adult plant during flower development. Both the late differentiation of the lineage producing germ cells, and the extent of gene expression during the haploid phase, may be incompatible with global resetting of methylation. Resetting may be unnecessary in any case because the adult plant expresses imprinted loci either biallelically or not at all, suggesting there is no chromosomal memory of parent-of-origin in the lineage that produces the gametophytes. Thus several features of the plant life cycle may account for the different strategies used by plants and animals to regulate parent-specific gene expression.     

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.     

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).     

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 cancer

Although we inherit two copies of all genes, except those that reside on the sex chromosomes, there is a subset of these genes in which only the paternal or maternal copy is functional. This phenomenon of monoallelic, parent-of-origin expression of genes is termed genomic imprinting. Imprinted genes are normally involved in embryonic growth and behavioral development, but occasionally they also function inappropriately as oncogenes and tumor suppressor genes. The evidence that imprinted genes play a role in carcinogenesis will be discussed in this review. Additional information about imprinted genes can be found on the Genomic Imprinting Website at: (http://www.geneimprint.com).     

Genomic imprinting in plant embryos

Genomic imprinting describes the expression of only one allele dependent on the parent-of-origin. This mechanism of monoallelic gene expression evolved independently in mammals and higher plants. Whereas in mammals, the phenomenon is known to affect extra-embryonic structures as well as the embryo, in plants imprinting seemed to be restricted to extra-embryonic, terminally differentiated tissue. The recent identification of parent-of-origin dependent gene expression in plant embryos indicates uncovered components and a more complex epigenetic regulatory system of genomic imprinting in plants.     

Genomic imprinting and conflict-induced decanalization

Genomic imprinting is the phenomenon in which the expression pattern of an allele depends on its parental origin. When maternally expressed and paternally expressed imprinted loci affect the same trait, the result is an arms race, with each locus under selection to increase its level of expression. This article develops a model of the deleterious consequences of this escalation, deriving from an increase in the variance in gene expression level, and resulting increase in phenotypic variance in the population. This phenomenon is referred to here as "conflict-induced decanalization." Modifiers that canalize gene expression are selectively favored, but these induce further escalation from both loci, resulting in a net increase in phenotypic variance and a reduction in population mean fitness. This results in a feedback loop, where increasing canalization of gene expression leads to increasing decanalization of the phenotype. This phenomenon may explain the surprisingly high frequency of certain diseases. Disorders to which this decanalization process might contribute include growth- and metabolism-related phenomena such as preterm birth, as well as certain major psychiatric disorders, including schizophrenia and autism.