Genomic imprinting in mammals.

Genomic Imprinting in Mammals Denise P. Barlow1 and Marisa S. Bartolomei2 1 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, CeMM, 1090 Vienna, Austria; 2 Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104-6148 Correspondence: and SUMMARY 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. Outline 1 Historical overview 2 Genomic imprinting—An epigenetic gene regulatory system 3 Key discoveries in genomic imprinting 4 Genomic imprinting—A model for mammalian epigenetic regulation 5 Future directions References Editors: C. David Allis, Marie-Laure Caparros, Thomas Jenuwein, and Danny Reinberg Additional Perspectives on Epigenetics available at www.cshperspectives.org Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a018382 Cite this article as Cold Spring Harb Perspect Biol 2014;6:a018382 1 D.P. Barlow and M.S. Bartolomei OVERVIEW Mammals are diploid organisms whose cells possess two matched sets of chromosomes, one inherited from the mother and one from the father. Thus, mammals have two copies of every gene. Normally both the maternal and paternal copy of each gene has the same potential to be active in any cell. Genomic imprinting is an epigenetic mechanism that changes this potential because it restricts the expression of a gene to one of the two parental chromosomes. It is a phenomenon displayed by only a few hundred of the approximately 25,000 genes in our genome, the majority being expressed equally when inherited from either parent. Genomic imprinting affects both male and female offspring and is therefore a consequence of parental inheritance, not of sex. As an example of what is meant by this, an imprinted gene that is active on a maternally inherited chromosome will be active on the maternal chromosome and silent on the paternal chromosome in all males and females. The definition of genomic imprinting is restricted here to “parental-specific gene expression in diploid cells.” Thus, diploid cells that contain two parental copies of all genes will express only one parental copy of an imprinted gene and silence the other parental copy. In contrast, nonimprinted genes will be expressed from both parental gene copies in a diploid cell. To understand the concept of genomic imprinting it is important to distinguish between imprinted genes and those showing apparent parental-specific expression because of unequal parental genetic contribution to the embryo. Examples of unequal parental genetic contribution include Y chromosome–linked genes present only in males, genes that escape X inactivation in females ( producing a double dose of X-linked gene products compared with males), mitochon- 2 drial genes contributed mainly by the maternal parent, and messenger RNAs (mRNAs) and proteins present only in the sperm or egg cytoplasm. Many features of genomic imprinting in mammals make it a fascinating biological problem in postgenomic times. It is intriguing that the subset of genes subject to genomic imprinting largely code for factors regulating embryonic and neonatal growth. Thus, it is likely that genomic imprinting evolved to play a specific role in mammalian reproduction. It is also providing clues as to a possible evolutionary response to parental conflict, to the adaptation of the maternal parent to an internal reproduction system, and, perhaps, providing a glimpse of the way the mammalian genome protects itself against invading DNA sequences. Genomic imprinting is an intellectually challenging phenomenon, not least because it raises the question of why a diploid organism would evolve a silencing system that forsakes the advantages of the diploid state. At this stage of our knowledge, genomic imprinting does not appear to be widespread among the four eukaryotic kingdoms that include Protista, Fungi, Plants, and Animals. However, it does exist, in a possibly related form, in two invertebrate arthropods—Coccidae and Sciaridae, and in the endosperm of some seed-bearing plants, such as maize and Arabidopsis. This distribution indicates that genomic imprinting arose independently at least three times during the evolution of life. Surprisingly, despite this predicted independent evolution of genomic imprinting, some similarities among the imprinting mechanism are emerging. It is likely that this reflects conservation of basic epigenetic regulatory mechanisms that underlie both genomic imprinting and normal gene regulation. Cite this article as Cold Spring Harb Perspect Biol 2014;6:a018382 Genomic Imprinting in Mammals 1 HISTORICAL OVERVIEW The presence of genomic imprinting in mammals has considerable medical, societal, and intellectual implications in terms of (1) the clinical management of genetic traits and diseases, (2) the capacity to control human and animal breeding by assisted reproductive technologies, and (3) the progress of biotechnology and postgenomic medical research. Any modern day discussion of genetic problems, whether in research or medicine, must consider if a gene shows a biparental (i.e., diploid) mode of expression, or, is subject to genomic imprinting and shows parental-specific (i.e., haploid) expression. Despite the importance of genomic imprinting to human health and well-being, it is surprising that widespread acceptance of its existence and significance did not happen until the early nineties after three genes were unequivocally shown to display parentalspecific expression in mice. Parental-specific behavior of whole chromosomes had been observed in cytogenetic studies of chromosomes in Arthropods as early as the 1930s (Chandra and Nanjundiah 1990). Interestingly, the term “chromosome imprinting” was first coined to describe paternal-specific chromosome elimination that plays a role in sex determination in some Arthropod species (Crouse et al. 1971). Chromosomal imprinting of the mammalian X chromosome was also noted, which leads to paternal-specific inactivation of one of the two X chromosomes in all cells of female marsupials and the extraembryonic tissues of the mouse (Cooper et al. 1971). During the same period, classical geneticists we (...truncated)