E S4) are dominated by a group of relatively unspecific terms

E S4) are dominated by a group of relatively unspecific terms related to transport processes such as organic cation transport, transmembrane transport, ion transport and organic cation transport. Therefore, not surprisingly, the five maternally expressed genes Kcnk9, Kcnq1, Slca22a2, Slca22a3 and Slca22a18 form a gene cluster that is associated with the same transportrelated GO terms. The second gene cluster is formed by TF genes including the maternally expressed genes Klf4 and Zim1 (Figure 4).Only few paternally expressed genes in human possess similar functionsThe 17 paternally expressed genes in human are associated with fewer over-represented GO terms (p,0.05) than the maternally expressed genes. Most of them were already present in the overrepresented terms for all imprinted genes (Figure 5 and Table S5). Thus we examined these genes on the basis of the GO_FAT knowledge base that contains more specific terms. Only two terms, i.e. regulation of transcription, DNA-dependent and regulation of RNA metabolic process are enriched for paternally expressed genes. Both terms are associated with the genes PLAGL1, L3MBTL, IGF2, WT1, ZIM2, and PEG3 (table S6). Hence, both maternally and paternally expressed genes contain prominent groups of genes that have regulatory roles. Paternally expressed genes in mouse did not show any significant enrichment.Maternally expressed genes dominate the role of imprinted genes in transport and gene regulationIn previous studies [6], we showed that maternally and paternally expressed genes differ in the level of conservation of their DNA sequences. For this reason, we analyzed whether maternally and paternally expressed genes differ also in their biological and molecular functions. For the 19 maternally expressed genes in human, only 3 broad Lixisenatide manufacturer functional terms were found to 23977191 be enriched, nervous system development, organ morphogenesis, and positive regulation of osteoblast differentiation. For the last GO term, the maternally expressed genes even showed a 59.4-fold enrichment (see table S4) although only two imprinted genes (DLX5 and GNAS) are associated with this term. Therefore, the enormousEnrichment analysis for the transcription factor targetsMammalian genes are usually controlled by combinations of different TFs that bind to distinct binding sites in regulatory regions such as the promoters of genes. We were interested in the questions which TFs regulate imprinted genes and if paternally and maternally expressed genes can be distinguished by their TFs. For addressing these questions we applied a similar enrichment analysis (see Methods) to investigate whether binding sites for distinct TFs are enriched in the promoter regions of imprinted genes. This analysis was based on a database of TF targets namedCellular Functions of Genetically Imprinted GenesFigure 2. Functionally related imprinted genes in human. The heat map view shows the gene-term association for those genes that share a high number of associated GO terms. Marked in red on the left side are maternally expressed genes; marked in blue are paternally expressed genes. doi:10.1371/journal.pone.0050285.64849-39-4 site gMolecular signature Database (MsigDB) [14]. This data set consists of sets of genes, the so-called TF targets families, that share binding sites for the same transcription factor families. In total, we identified 25 TF families that showed an enrichment of binding sites in the set of imprinted genes in human (p,0.01, hyper-geometric test, see Methods).E S4) are dominated by a group of relatively unspecific terms related to transport processes such as organic cation transport, transmembrane transport, ion transport and organic cation transport. Therefore, not surprisingly, the five maternally expressed genes Kcnk9, Kcnq1, Slca22a2, Slca22a3 and Slca22a18 form a gene cluster that is associated with the same transportrelated GO terms. The second gene cluster is formed by TF genes including the maternally expressed genes Klf4 and Zim1 (Figure 4).Only few paternally expressed genes in human possess similar functionsThe 17 paternally expressed genes in human are associated with fewer over-represented GO terms (p,0.05) than the maternally expressed genes. Most of them were already present in the overrepresented terms for all imprinted genes (Figure 5 and Table S5). Thus we examined these genes on the basis of the GO_FAT knowledge base that contains more specific terms. Only two terms, i.e. regulation of transcription, DNA-dependent and regulation of RNA metabolic process are enriched for paternally expressed genes. Both terms are associated with the genes PLAGL1, L3MBTL, IGF2, WT1, ZIM2, and PEG3 (table S6). Hence, both maternally and paternally expressed genes contain prominent groups of genes that have regulatory roles. Paternally expressed genes in mouse did not show any significant enrichment.Maternally expressed genes dominate the role of imprinted genes in transport and gene regulationIn previous studies [6], we showed that maternally and paternally expressed genes differ in the level of conservation of their DNA sequences. For this reason, we analyzed whether maternally and paternally expressed genes differ also in their biological and molecular functions. For the 19 maternally expressed genes in human, only 3 broad functional terms were found to 23977191 be enriched, nervous system development, organ morphogenesis, and positive regulation of osteoblast differentiation. For the last GO term, the maternally expressed genes even showed a 59.4-fold enrichment (see table S4) although only two imprinted genes (DLX5 and GNAS) are associated with this term. Therefore, the enormousEnrichment analysis for the transcription factor targetsMammalian genes are usually controlled by combinations of different TFs that bind to distinct binding sites in regulatory regions such as the promoters of genes. We were interested in the questions which TFs regulate imprinted genes and if paternally and maternally expressed genes can be distinguished by their TFs. For addressing these questions we applied a similar enrichment analysis (see Methods) to investigate whether binding sites for distinct TFs are enriched in the promoter regions of imprinted genes. This analysis was based on a database of TF targets namedCellular Functions of Genetically Imprinted GenesFigure 2. Functionally related imprinted genes in human. The heat map view shows the gene-term association for those genes that share a high number of associated GO terms. Marked in red on the left side are maternally expressed genes; marked in blue are paternally expressed genes. doi:10.1371/journal.pone.0050285.gMolecular signature Database (MsigDB) [14]. This data set consists of sets of genes, the so-called TF targets families, that share binding sites for the same transcription factor families. In total, we identified 25 TF families that showed an enrichment of binding sites in the set of imprinted genes in human (p,0.01, hyper-geometric test, see Methods).