Endosperm imprinting: a child custody battle?

Endosperm gene imprinting has long been speculated to control nutrient allocation to seeds. For the first time, an imprinted gene directly involved in this process has been identified.     

Controlling X-inactivation in mammals: what does the centre hold?

Controlling gene expression is one of the most fundamental task of living organisms, from prokaryotes to higher eukaryotes, in order to develop, grow, and reproduce in an ever changing environment. In many cases, the expression status of a given gene is controlled independently of that of its neighbours through localised cis DNA elements responsible for the recruitment of specific factors and enzymatic activities. However, in a growing number of cases, genomic regions including several genes have been shown to be regulated in a coordinated manner. X-chromosome inactivation, the dosage compensation mechanism encountered in mammals, is one of the most Striking example of such coordinated gene regulation. This process, which occurs at the chromosome-wide level, affecting many hundreds of genes, is under the control of a unique, cis acting region, termed the X-inactivation centre, whose complexity is just beginning to be unravelled.     

Is it genomic imprinting or preferential expression?

Imprinted genes are monoallelically expressed in a parent-of-origin-specific manner, but for many genes reported to be imprinted, the occurrence of preferential expression--where both alleles are expressed but one is expressed more strongly than the other in a parent-of-origin-specific way--has been reported. This preferential expression found in genes described as imprinted has not been thoroughly addressed in genomic imprinting studies. To study this phenomenon, 50 genes, reported to be imprinted in the mouse, were chosen for investigation. Preferential expression was observed for 21 of 27 maternally expressed genes. However, only 5 of 23 paternally expressed genes showed preferential expression. Recently, it has been reported that a remarkable proportion of non-imprinted genes show differential allelic expression. If there is overlap between non-imprinted genes that are differentially expressed and imprinted genes that are preferentially expressed, we need to set new definitions of imprinted genes that, in turn, would probably lead to reassessments of the total number of imprinted genes in mammalian species.     

Too large to fit? Recent developments in macromolecular imprinting

Molecular imprinting involves the synthesis of polymers in the presence of a template to produce complementary binding sites with specific recognition ability. The technique has been successfully applied as a measurement and separation technology, producing a uniquely robust and antibody-like polymeric material. Low molecular weight molecules have been extensively exploited as imprint templates, leading to significant achievements in solid-phase extraction, sensing and enzyme-like catalysis. By contrast, macromolecular imprinting remains underdeveloped, principally because of the lack of binding site accessibility. In this review, we focus on the most recent developments in this area, not only covering the widespread use of biological macro-templates but also highlighting the emerging use of synthetic macro-templates, such as dendrimers and hyperbranched polymers.     

Epigenetics: imprinting in plants and mammals--the same but different?

Plants and animals both exhibit parental imprinting, but do they control it the same way? Recent studies show that in Arabidopsis, as in mammals, imprinted alleles are subject to DNA methylation--but, surprisingly, the default state is silence rather than activity.     

Does random X-inactivation in mammals reflect a random choice between two X chromosomes?

Inactivation of the maternal or paternal X chromosome in a mammalian embryonic XX cell is believed to involve random choice between the two X's. We propose two alternative models. One suggests that choice is not random, while the other is consistent with random choice, but not one between two X's.     

Maternal–fetal conflict,genomic imprinting and mammalian vulnerabilities to cancer

Antagonistic coevolution between maternal and fetal genes, and between maternally and paternally derived genes may have increased mammalian vulnerability to cancer. Placental trophoblast has evolved to invade maternal tissues and evade structural and immunological constraints on its invasion. These adaptations can be co-opted by cancer in intrasomatic selection. Imprinted genes of maternal and paternal origin favour different degrees of proliferation of particular cell types in which they reside. As a result, the set of genes favouring greater proliferation will be selected to evade controls on cell-cycle progression imposed by the set of genes favouring lesser proliferation. The dynamics of stem cell populations will be a particular focus of this intragenomic conflict. Gene networks that are battlegrounds of intragenomic conflict are expected to be less robust than networks that evolve in the absence of conflict. By these processes, maternal–fetal and intragenomic conflicts may undermine evolved defences against cancer.     

X-inactivation analysis of embryonic lethality in Ocrl wt/−;Inpp5b −/− mice

Mutations in the human OCRL gene, which encodes a phosphatidylinositol(4,5)bisphosphate 5-phosphatase, result in the X-linked oculocerebrorenal syndrome of Lowe. Mice with a targeted disruption of Ocrl have no phenotypic abnormalities. Targeted disruption of its closest paralog, Inpp5b, causes male infertility in the 129S6 background. Mice with disruptions of both genes are lost in utero prior to 9.5-10.5 dpc, indicating that there is a functional overlap between the two paralogs early in development. We analyzed the pattern of X-inactivation in four tissues of distinct embryonic origin from Ocrl ^wt/?;Inpp5b ^?/? females to explore the timing and tissue distribution of the functional overlap. X-inactivation was strongly skewed against the disrupted Ocrl ^? allele being on the active X chromosome in all four tissues tested, indicating that there is early selection against cell lineages lacking both Ocrl and Inpp5b. Extraembryonic tissue was also involved in the lethality because there were never any live-born Ocrl ^wt/?;Inpp5b ^?/? females when the functional Ocrl ^wt allele was on the paternal X chromosome, which is preferentially inactivated in trophoblast-derived extraembryonic tissues. Live-born Ocrl ^wt/?;Inpp5b ^?/? females were found when the functional Ocrl ^wt allele was maternal, although in fewer numbers than expected. The importance of the extraembryonic tissues in the early embryonic lethality of embryos lacking both Ocrl and Inpp5b is reinforced by the successful isolation of a viable 40,XX Ocrl ^?/?;Inpp5b ^?/? embryonic stem cell from the inner cell mass of a 3.5-dpc blastocyst prior to implantation. These results indicate a functional overlap of Ocrl and Inpp5b in most cell lineages, especially in extraembryonic tissues.     

Genomic imprinting: A missing piece of the Multiple Sclerosis puzzle?

Evidence for parent-of-origin effects in complex diseases such as Multiple Sclerosis (MS) strongly suggests a role for epigenetic mechanisms in their pathogenesis. In this review, we describe the importance of accounting for parent-of-origin when identifying new risk variants for complex diseases and discuss how genomic imprinting, one of the best-characterized epigenetic mechanisms causing parent-of-origin effects, may impact etiology of complex diseases. While the role of imprinted genes in growth and development is well established, the contribution and molecular mechanisms underlying the impact of genomic imprinting in immune functions and inflammatory diseases are still largely unknown. Here we discuss emerging roles of imprinted genes in the regulation of inflammatory responses with a particular focus on the Dlk1 cluster that has been implicated in etiology of experimental MS-like disease and Type 1 Diabetes. Moreover, we speculate on the potential wider impact of imprinting via the action of imprinted microRNAs, which are abundantly present in the Dlk1 locus and predicted to fine-tune important immune functions. Finally, we reflect on how unrelated imprinted genes or imprinted genes together with non-imprinted genes can interact in so-called imprinted gene networks (IGN) and suggest that IGNs could partly explain observed parent-of-origin effects in complex diseases. Unveiling the mechanisms of parent-of-origin effects is therefore likely to teach us not only about the etiology of complex diseases but also about the unknown roles of this fascinating phenomenon underlying uneven genetic contribution from our parents.This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease.     

X-inactivation pattern in carriers of X-linked retinitis pigmentosa: A valuable means of prognostic evaluation?

In a large family with X-linked retinitis pigmentosa 2 (XLRP2), we reexamined 7 obligate carrier females and 6 daughters of obligate carriers, whose linkage relationships suggested that they carried the XLRP2 gene. The phenotype varied from totally normal eyes through mild retinal changes to complete loss of vision. The X-inactivation analysis was carried out with the highly informative probe M27 on DNA from blood lymphocytes. This probe detects a locus DXS 255 that is differentially methylated on the active and inactive X chromosomes. In 5 blind heterozygotes (aged 43 to 68 years), we found that the X chromosome carrying the RP2 gene was methylated and active in nearly all their cells. The opposite X inactivation pattern was found in a carrier female (aged 45 years) who gave normal findings on eye examination. Carriers with less skewed X inactivation had a less severe clinical outcome. However, we found little or no correlation between their phenotypes and the methylation status of their X chromosomes. Our results suggest that it may be possible to develop a predictive test that could identify cases with severe outcome and perhaps cases with normal outcome.     

Genomic imprinting in mammals: an interplay between chromatin and DNA methylation?

Most imprinted loci have key regulatory elements that are methylated on only one of the parental chromosomes. For several of these 'differentially methylated regions', recent studies establish that the unmethylated chromosome has a specialized chromatin organization that is characterized by nuclease hypersensitivity. The novel data raise the question of whether specific proteins and associated chromatin features regulate the allele-specificity of DNA methylation at these imprinting control elements.     

Studies of hormone evolution. Can non-hormone oligopeptides induce a functional imprinting?

Certain non-hormone oligopeptides have a greater imprinting effect on Tetrahymena than others. The imprinting potential is unrelated to the length of the peptide chain, but seems greatly dependent on the amino acid sequence. The direct growth-stimulant action developed by the peptides at the first interaction is unrelated to their imprinting effect.     

Germline imprinting: battle of the sexes or battle of the X's?

The X chromosome is largely inactivated in spermatogenesis of heterogametic males, and in multiple phyla it encodes few genes specifically expressed in the male germline. Writing in Nature Genetics, Bean et al. report a parallel between male germline X inactivation in nematodes and a fungal gene-silencing mechanism that alters the way we view the evolution of both phenomena.