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Cellular Functions of Genetically Imprinted Genes in Human and Mouse As Annotated in the Gene Ontology

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Cellular Functions of Genetically Imprinted Genes in Human and Mouse As Annotated in the Gene Ontology Cellular Functions of Genetically Imprinted Genes in Human and Mouse as Annotated in the Gene Ontology Mohamed Hamed1, Siba Ismael1, Martina Paulsen2, Volkhard Helms1* 1 Center for Bioinformatics, Saarland University, Saarbru¨cken, Germany, 2 Department of Genetics, Saarland University, Saarbru¨cken, Germany Abstract By analyzing the cellular functions of genetically imprinted genes as annotated in the Gene Ontology for human and mouse, we found that imprinted genes are often involved in developmental, transport and regulatory processes. In the human, paternally expressed genes are enriched in GO terms related to the development of organs and of anatomical structures. In the mouse, maternally expressed genes regulate cation transport as well as G-protein signaling processes. Furthermore, we investigated if imprinted genes are regulated by common transcription factors. We identified 25 TF families that showed an enrichment of binding sites in the set of imprinted genes in human and 40 TF families in mouse. In general, maternally and paternally expressed genes are not regulated by different transcription factors. The genes Nnat, Klf14, Blcap, Gnas and Ube3a contribute most to the enrichment of TF families. In the mouse, genes that are maternally expressed in placenta are enriched for AP1 binding sites. In the human, we found that these genes possessed binding sites for both, AP1 and SP1. Citation: Hamed M, Ismael S, Paulsen M, Helms V (2012) Cellular Functions of Genetically Imprinted Genes in Human and Mouse as Annotated in the Gene Ontology. PLoS ONE 7(11): e50285. doi:10.1371/journal.pone.0050285 Editor: Osman El-Maarri, University of Bonn, Institut of experimental hematology and transfusion medicine, Germany Received June 23, 2012; Accepted October 23, 2012; Published November 30, 2012 Copyright: ß 2012 Hamed et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported was supported by scholarships to MH and SI via the German Academic Exchange Service (DAAD) and by a grant by the Deutsche Forschungsgemeinschaft (PA 750/3-1). The funders had no role in study design, data collection and analysis,decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] Introduction The evolution of a gene regulatory mechanism that silences preferentially one parental allele of a gene implies that paternally Genomic imprinting is an epigenetic phenomenon observed in and maternally expressed genes experience different selective eutherian mammals. For the large majority of autosomal genes, pressures during evolution. This assumption is supported by the the two parental copies are both either transcribed or silent. finding that the two groups reveal different patterns of sequence However, in a small group of genes one copy is turned off in a conservation. Whereas the protein-encoding DNA sequences of parent-of-origin specific manner thereby resulting in monoallelic paternally expressed genes are well conserved among different expression. These genes are called ‘imprinted’ because the silenced mammalian species, maternally expressed genes are much more copy of the gene is epigenetically marked or imprinted in either the divergent [6]. Whether paternally and maternally expressed genes egg or the sperm [1]. differ also in molecular functions and gene regulation is a question Imprinted genes play important roles in development and that has not yet been investigated in detail. Many studies showed growth both pre- and postnatally by acting in fetal and placental that imprinted genes are not only important during embryonic tissues [2]. Interestingly, there appears to exist a general pattern development but possess also postnatal functions. Hence, kinship whereby maternally expressed genes tend to limit embryonic theory with its focus on prenatal development might explain some growth and paternally expressed genes tend to promote growth. A but not all aspects of the evolution of genomic imprinting. model case for this striking scenario is the antagonistic action of During postnatal development, genomic imprinting affects Igf2 and Igf2r in mouse. Deletion of the paternally expressed Igf2 endocrinal networks, energy metabolism, and behavior. Promi- gene results in intrauterine growth restriction. On the other hand, nent examples for the functions of imprinted genes in endocrinal deletion of the maternally expressed gene Igf2r, results in pathways are the imprinted transcripts of the Gnas locus. In the overgrowth [3]. human, genetic and epigenetic aberrations in this region are The observation that maternally and paternally expressed genes associated with Albright hereditary osteodystrophy and pseudo- apparently act as antagonists has inspired several evolutionary hypoparathyroidism type 1A or 1B [7]. Behavioral abnormalities theories that aim to explain the origin of genetic imprinting under have been observed in human imprinting disorders and in various the process of ‘natural selection’ [2]. The most scientifically mouse models in which imprinted genes have been mutated. For accepted theory is currently the kinship theory [4] and [5]. Briefly, example, the obesity of Prader-Willi-syndrome patients is, at least this theory suggests that in polygamous mammalian species, silencing of maternally derived growth inhibiting genes results in in parts, a result of an impaired eating behavior. Knock-out studies increased growth of the embryo. This is associated with an in mouse showed that the two paternally expressed Peg1 and Peg3 increased nutritional demand and thereby with an exploitation of genes have a clear behavioral phenotype [8]. Females that inherit maternal resources at the cost of future off-spring that might be a null allele for these genes from their fathers behaved ‘deficiently’ fathered by a different male. PLOS ONE | www.plosone.org 1 November 2012 | Volume 7 | Issue 11 | e50285 Cellular Functions of Genetically Imprinted Genes with respect to maternal care behavior including placentophagy map enrichment plugin in Cytoscape [11] was used to visualize the and nest-building as well as pup gathering. overrepresented functional terms and display the overlapping As the phenomenon of genomic imprinting is an important functional sets. evolutionary facet of mammals with placentas, it is of great interest to identify which sorts of cellular and developmental processes of Gene Functional clustering developing and/or mature organisms are subject to control by Clustering and grouping of the imprinted genes were performed imprinted genes. We aimed in this study at characterizing the using the DAVID gene functional classification tool. This tool cellular roles of imprinted genes in an unbiased, data-driven employs a set of fuzzy clustering techniques to classify input genes approach. For this, we used the gene annotations of the Gene into functionally related gene groups (or classes). This is done on Ontology (GO) that consists of three structured and controlled the basis of the co-occurrence of annotation terms by generating a vocabularies for the biological processes, cellular components, and gene-to-gene similarity matrix based on shared functional anno- molecular functions associated with particular genes. As it is of tation. This switches the functional annotation analysis from a particular interest to analyze which of these functions are gene-centric analysis to a biological module-centric analysis [10]. controlled by the sets of maternally and paternally expressed The similarity threshold was set to the minimum similarity genes, we have also separately analyzed the enrichment of GO threshold of 0.3 suggested by the DAVID consortium. This is then terms in these two groups. the minimum value to be considered by the similarity-matching algorithm as biologically significant. Also, we set the minimum Methods gene number in a seeding group to 2. This would be the minimum Gene Selection size of each cluster in the final results. All remaining parameters were kept to their default values. The results of the functional Imprinted genes of human and mouse were downloaded from classification tool are visualized as heat maps to show the the Catalogue of Imprinted Genes and Parent-of-origin Effects in corresponding gene-annotation association across the clustered Humans and Animals (IGC) [9] and [2]. The catalogue genes. encompasses genes that were described as being imprinted in literature. As the related experiments were done in many different labs, the experimental procedures differed considerably. After Transcription Factor Target Enrichment reading the original publications, we manually selected 64 The web-based gene set analysis toolkit WebGestalt [12] was imprinted genes that are imprinted without doubt in at least one used to analyze the targets of transcription factors (TFs), see tables of the two species, see table S1. For the gene C15orf2, the S7 and S8. This tool incorporates information from different expressed allele is unknown since there is no information on the public resources such as NCBI Gene, GO, KEGG and MsigDB parental origin of the alleles. Copg2, and Zim2 are paternally (http://bioinfo.vanderbilt.edu/webgestalt/). Using the TF target expressed in the human, but maternally expressed in the mouse.
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