ORCID Profile
0000-0002-5716-8838
Current Organisation
Shinshu University
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Publisher: Oxford University Press (OUP)
Date: 23-06-2022
DOI: 10.1093/GBE/EVAC094
Abstract: Genomic imprinting is found in marsupial and eutherian mammals, but not in monotremes. While the primary regulator of genomic imprinting in eutherians is differential DNA methylation between parental alleles, conserved imprinted genes in marsupials tend to lack DNA methylation at their promoters. DNA methylation at eutherian imprinted genes is mainly catalyzed by a DNA methyltransferase (DNMT) enzyme, DNMT3A. There are two isoforms of eutherian DNMT3A: DNMT3A and DNMT3A2. DNMT3A2 is the primary isoform for establishing DNA methylation at eutherian imprinted genes and is essential for eutherian genomic imprinting. In this study, we investigated whether DNMT3A2 is also present in the two other mammalian lineages, marsupials and monotremes. We identified DNMT3A2 in both marsupials and monotremes, although imprinting has not been identified in monotremes. By analyzing genomic sequences and transcriptome data across vertebrates, we concluded that the evolution of DNMT3A2 occurred in the common ancestor of mammals. In addition, DNMT3A/3A2 gene and protein expression during gametogenesis showed distinct sexual dimorphisms in a marsupial, the tammar wallaby, and this pattern coincided with the sex-specific DNA methylation reprogramming in this species as it does in mice. Our results show that DNMT3A2 is present in all mammalian groups and suggests that the basic DNMT3A/3A2-based DNA methylation mechanism is conserved at least in therian mammals.
Publisher: Oxford University Press (OUP)
Date: 07-07-2016
DOI: 10.1093/GBE/EVW156
Publisher: Portland Press Ltd.
Date: 09-02-2015
DOI: 10.1042/BJ20150926
Abstract: FABPs (fatty-acid-binding proteins) are a family of low-molecular-mass intracellular lipid-binding proteins consisting of ten isoforms. FABPs are involved in binding and storing hydrophobic ligands such as long-chain fatty acids, as well as transporting these ligands to the appropriate compartments in the cell. FABP5 is overexpressed in multiple types of tumours. Furthermore, up-regulation of FABP5 is strongly associated with poor survival in triple-negative breast cancer. However, the mechanisms underlying the specific up-regulation of the FABP5 gene in these cancers remain poorly characterized. In the present study, we determined that FABP5 has a typical CpG island around its promoter region. The DNA methylation status of the CpG island in the FABP5 promoter of benign prostate cells (PNT2), prostate cancer cells (PC-3, DU-145, 22Rv1 and LNCaP) and human normal or tumour tissue was assessed by bisulfite sequencing analysis, and then confirmed by COBRA (combined bisulfite restriction analysis) and qAMP (quantitative analysis of DNA methylation using real-time PCR). These results demonstrated that overexpression of FABP5 in prostate cancer cells can be attributed to hypomethylation of the CpG island in its promoter region, along with up-regulation of the direct trans-acting factors Sp1 (specificity protein 1) and c-Myc. Together, these mechanisms result in the transcriptional activation of FABP5 expression during human prostate carcinogenesis. Importantly, silencing of Sp1, c-Myc or FABP5 expression led to a significant decrease in cell proliferation, indicating that up-regulation of FABP5 expression by Sp1 and c-Myc is critical for the proliferation of prostate cancer cells.
Publisher: Oxford University Press (OUP)
Date: 23-05-2013
Publisher: Springer Science and Business Media LLC
Date: 08-05-2019
DOI: 10.1007/S00439-019-02017-5
Abstract: Tandem repeats (TRs) are widespread in the genomes of all living organisms. In eukaryotes, they are found in both coding and noncoding regions and have potential roles in the regulation of cellular processes such as transcription, translation and in the modification of protein structure. Recent studies have highlighted TRs as a key regulator of gene expression and a potential contributor to human evolution. Thus, TRs are emerging as an important source of variation that can result in differential gene expression at intra- and inter-species levels. In this study, we performed a genome-wide survey to identify TRs that have emerged in the human lineage. We further examined these loci to explore their potential functional significance for human evolution. We identified 152 human-specific TR (HSTR) loci containing a repeat unit of more than ten bases, with most of them showing a repeat count of two. Gene set enrichment analysis showed that HSTR-associated genes were associated with biological functions in brain development and synapse function. In addition, we compared gene expression of human HSTR loci with orthologues from non-human primates (NHP) in seven different tissues. Strikingly, the expression level of HSTR-associated genes in brain tissues was significantly higher in human than in NHP. These results suggest the possibility that de novo emergence of TRs could have resulted in altered gene expression in humans within a short-time frame and contributed to the rapid evolution of human brain function.
Publisher: The Royal Society
Date: 05-01-2013
Abstract: Genomic imprinting is widespread in eutherian mammals. Marsupial mammals also have genomic imprinting, but in fewer loci. It has long been thought that genomic imprinting is somehow related to placentation and/or viviparity in mammals, although neither is restricted to mammals. Most imprinted genes are expressed in the placenta. There is no evidence for genomic imprinting in the egg-laying monotreme mammals, despite their short-lived placenta that transfers nutrients from mother to embryo. Post natal genomic imprinting also occurs, especially in the brain. However, little attention has been paid to the primary source of nutrition in the neonate in all mammals, the mammary gland. Differentially methylated regions (DMRs) play an important role as imprinting control centres in each imprinted region which usually comprises both paternally and maternally expressed genes ( PEG s and MEG s). The DMR is established in the male or female germline (the gDMR). Comprehensive comparative genome studies demonstrated that two imprinted regions, PEG10 and IGF2-H19 , are conserved in both marsupials and eutherians and that PEG10 and H19 DMRs emerged in the therian ancestor at least 160 Ma, indicating the ancestral origin of genomic imprinting during therian mammal evolution. Importantly, these regions are known to be deeply involved in placental and embryonic growth. It appears that most maternal gDMRs are always associated with imprinting in eutherian mammals, but emerged at differing times during mammalian evolution. Thus, genomic imprinting could evolve from a defence mechanism against transposable elements that depended on DNA methylation established in germ cells.
Publisher: Public Library of Science (PLoS)
Date: 13-04-2007
Publisher: Oxford University Press (OUP)
Date: 10-07-2012
Abstract: GRB10 is an imprinted gene differently expressed from two promoters in mouse and human. Mouse Grb10 is maternally expressed from the major promoter in most tissues and paternally expressed from the brain-specific promoter within specific regions of the fetal and adult central nervous system. Human GRB10 is biallelically expressed from the major promoter in most tissues except in the placental villus trophoblast where it is maternally expressed, whereas the brain-specific promoter is paternally expressed in the fetal brain. This study characterized the ortholog of GRB10 in a marsupial, the tammar wallaby (Macropus eugenii) to investigate the origin and evolution of imprinting at this locus. The protein coding exons and predicted amino acid sequence of tammar GRB10 were highly conserved with eutherian GRB10. The putative first exon, which is located in the orthologous region to the eutherian major promoter, was found in the tammar, but no exon was found in the downstream region corresponding to the eutherian brain-specific promoter, suggesting that marsupials only have a single promoter. Tammar GRB10 was widely expressed in various tissues including the brain but was not imprinted in any of the tissues examined. Thus, it is likely that GRB10 imprinting evolved in eutherians after the eutherian-marsupial ergence approximately 160 million years ago, subsequent to the acquisition of a brain-specific promoter, which resides within the imprinting control region in eutherians.
Publisher: Springer Science and Business Media LLC
Date: 19-08-2011
Abstract: Genomic imprinting causes parent-of-origin specific gene expression by differential epigenetic modifications between two parental genomes. We previously reported that there is no evidence of genomic imprinting of CDKN1C in the KCNQ1 domain in the placenta of an Australian marsupial, the tammar wallaby ( Macropus eugenii ) whereas tammar IGF2 and H19 , located adjacent to the KCNQ1 domain in eutherian mammals, are imprinted. We have now identified and characterised the marsupial orthologue of PHLDA2 , another gene in the KCNQ1 domain (also known as IPL or TSSC3 ) that is imprinted in eutherians. In mice, Phlda2 is a dose-sensitive negative regulator of placental growth, as Cdkn1c is for embryonic growth. Tammar PHLDA2 is highly expressed in the yolk sac placenta compared to other fetal tissues, confirming a similar expression pattern to that of mouse Phlda2 . However, tammar PHLDA2 is biallelically expressed in both the fetus and yolk sac placenta, so it is not imprinted. The lack of imprinting in tammar PHLDA2 suggests that the acquisition of genomic imprinting of the KCNQ1 domain in eutherian mammals, accompanied with gene dosage reduction, occurred after the split of the therian mammals into the marsupials and eutherians. Our results confirm the idea that acquisition of genomic imprinting in the KCNQ1 domain occurred specifically in the eutherian lineage after the ergence of marsupials, even though imprinting of the adjacent IGF2-H19 domain arose before the marsupial-eutherian split. These data are consistent with the hypothesis that genomic imprinting of the KCNQ1 domain may have contributed to the evolution of more complex placentation in the eutherian lineage by reduction of the gene dosage of negative regulators for both embryonic and placental growth.
Publisher: Elsevier BV
Date: 09-2007
DOI: 10.1016/J.YDBIO.2007.07.025
Abstract: Therian mammals (marsupials and eutherians) rely on a placenta for embryo survival. All mammals have a yolk sac, but while both chorio-allantoic and chorio-vitelline (yolk sac) placentation can occur, most marsupials only develop a yolk sac placenta. Insulin (INS) is unusual in that it is the only gene that is imprinted exclusively in the yolk sac placenta. Marsupials, therefore, provide a unique opportunity to examine the conservation of INS imprinting in mammalian yolk sac placentation. Marsupial INS was cloned and its imprint status in the yolk sac placenta of the tammar wallaby, Macropus eugenii, examined. In two informative in iduals of the eight that showed imprinting, INS was paternally expressed. INS protein was restricted to the yolk sac endoderm, while insulin receptor, IR, protein was additionally expressed in the trophoblast. INS protein increased during late gestation up to 2 days before birth, but was low the day before and on the day of birth. The conservation of imprinted expression of insulin in the yolk sac placenta of ergent mammalian species suggests that it is of critical importance in the yolk sac placenta. The restriction of imprinting to the yolk sac suggests that imprinting of INS evolved in the chorio-vitelline placenta independently of other tissues in the therian ancestor of marsupials and eutherians.
Publisher: Springer Science and Business Media LLC
Date: 08-03-2017
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.BBRC.2018.07.066
Abstract: The evolutionary conserved genomic sequences that have acquired significantly increased number of nucleotide substitutions specifically in the human lineage, called human accelerated regions (HARs), have been identified as candidate genomic regions that have contributed to the evolution of human-specific traits. A number of HARs were indeed shown to have novel enhancer activity and be associated with human-specific brain development and with cognition and social behavior. It is therefore of great importance to investigate the details of genomic function of each HAR to understand the roles of HARs as critical contributors to the genetic basis of human evolution. In this study, we identified a previously unannotated brain-expressed noncoding RNA gene, HSTR1, at a human-specific tandem repeat locus. Notably, the 5' flanking sequence of HSTR1 showed the signature of HARs and the dramatic human-specific enhancement of promoter activity, providing the evidence of positive selection to increase the expression level of HSTR1 during human evolution. We also revealed that the tandem repeat number in HSTR1 was highly variable among in idual alleles and affected the stability of HSTR1 RNA, suggesting variation in the activity of HSTR1 between human in iduals. Our work thus provides a novel candidate gene that potentially contributed to the evolution of the human brain. It may also underpin some of the variation between human brains.
Publisher: Oxford University Press (OUP)
Date: 2011
DOI: 10.1093/GBE/EVR104
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1016/J.MOD.2004.10.003
Abstract: Genomic imprinting is widespread amongst mammals, but has not yet been found in birds. To gain a broader understanding of the origin and significance of imprinting, we have characterized three genes, from three separate imprinted clusters in eutherian mammals in the developing fetus and placenta of an Australian marsupial, the tammar wallaby Macropus eugenii. Imprinted gene orthologues of human and mouse p57(KIP2), IGF2 and PEG1/MEST genes were isolated. p57(KIP2) did not show stable monoallelic expression suggesting that it is not imprinted in marsupials. In contrast, there was paternal-specific expression of IGF2 in almost all tissues, but the biased paternal expression of IGF2 in the fetal head and placenta, demonstrates the occurrence of tissue-specific imprinting, as occurs in mice and humans. There was also paternal-biased expression of PEG1/MESTalpha. The differentially methylated region (DMR) of the human and mouse PEG1/MEST promoter is absent in the wallaby. These data confirm the existence of common imprinted regions in eutherians and marsupials during development, but suggest that the regulatory mechanisms that control imprinted gene expression differ between these two groups of mammals.
Publisher: Frontiers Media SA
Date: 10-03-2022
DOI: 10.3389/FCELL.2022.838684
Abstract: Genomic imprinting, parent-of-origin-specific gene expression, is controlled by differential epigenetic status of the parental chromosomes. While DNA methylation and suppressive histone modifications established during gametogenesis suppress imprinted genes on the inactive allele, how and when the expressed allele gains its active status is not clear. In this study, we asked whether the active histone-3 lysine-4 trimethylation (H3K4me3) marks remain at paternally expressed genes (PEGs) in sperm and embryos before and after fertilization using published data. Here we show that mouse sperm had the active H3K4me3 at more than half of known PEGs, and these genes were present even after fertilization. Using reciprocal cross data, we identified 13 new transient PEGs during zygotic genome activation. Next, we confirmed that the 12 out of the 13 new transient PEGs were associated with the paternal H3K4me3 in sperm. Nine out of the 12 genes were associated with the paternal H3K4me3 in zygotes. Our results show that paternal H3K4me3 marks escape inactivation during the histone-to-protamine transition that occurs during sperm maturation and are present in embryos from early zygotic stages up to implantation.
Publisher: Public Library of Science (PLoS)
Date: 25-07-2012
Publisher: Springer Science and Business Media LLC
Date: 28-08-2012
Abstract: In marsupials, growth and development of the young occur postnatally, regulated by milk that changes in composition throughout the long lactation. To initiate lactation in mammals, there is an absolute requirement for insulin ( INS ), a gene known to be imprinted in the placenta. We therefore examined whether INS is imprinted in the mammary gland of the marsupial tammar wallaby ( Macropus eugenii ) and compared its expression with that of insulin-like growth factor 2 ( IGF2 ). INS was expressed in the mammary gland and significantly increased, while IGF2 decreased, during established milk production. Insulin and IGF2 were both detected in the mammary gland macrophage cells during early lactation and in the alveolar cells later in lactation. Surprisingly, INS , which was thought only to be imprinted in the therian yolk sac, was imprinted and paternally expressed in the liver of the developing young, monoallelically expressed in the tammar mammary gland and biallelic in the stomach and intestine. The INS transcription start site used in the liver and mammary gland was differentially methylated. This is the first study to identify tissue-specific INS imprinting outside the yolk sac. These data suggest that there may be an advantage of selective monoallelic expression in the mammary gland and that this may influence the growth of the postnatal young. These results are not consistent with the parental conflict hypothesis, but instead provide support for the maternal–infant co-adaptation hypothesis. Thus, imprinting in the mammary gland maybe as critical for postnatal growth and development in mammals as genomic imprinting in the placenta is prenatally.
Publisher: Springer Science and Business Media LLC
Date: 27-08-2022
DOI: 10.1186/S13072-022-00465-4
Abstract: The eutherian IGF2R imprinted domain is regulated by an antisense long non-coding RNA, Airn , which is expressed from a differentially methylated region (DMR) in mice. Airn silences two neighbouring genes, Solute carrier family 22 member 2 ( Slc22a2) and Slc22a3 , to establish the Igf2r imprinted domain in the mouse placenta. Marsupials also have an antisense non-coding RNA, ALID , expressed from a DMR, although the exact function of ALID is currently unknown. The eutherian IGF2R DMR is located in intron 2, while the marsupial IGF2R DMR is located in intron 12, but it is not yet known whether the adjacent genes SLC22A2 and/or SLC22A3 are also imprinted in the marsupial lineage. In this study, the imprinting status of marsupial SLC22A2 and SLC22A3 in the IGF2R imprinted domain in the chorio-vitelline placenta was examined in a marsupial, the tammar wallaby. In the tammar placenta, SLC22A3 but not SLC22A2 was imprinted. Tammar SLC22A3 imprinting was evident in placental tissues but not in the other tissues examined in this study. A putative promoter of SLC22A3 lacked DNA methylation, suggesting that this gene is not directly silenced by a DMR on its promoter as seen in the mouse. Based on immunofluorescence, we confirmed that the tammar SLC22A3 is localised in the endodermal cell layer of the tammar placenta where nutrient trafficking occurs. Since SLC22A3 is imprinted in the tammar placenta, we conclude that this placental imprinting of SLC22A3 has been positively selected after the marsupial and eutherian split because of the differences in the DMR location. Since SLC22A3 is known to act as a transporter molecule for nutrient transfer in the eutherian placenta, we suggest it was strongly selected to control the balance between supply and demand of nutrients in marsupial as it does in eutherian placentas.
Publisher: Springer Science and Business Media LLC
Date: 03-06-2013
Publisher: Springer Science and Business Media LLC
Date: 29-09-2018
No related grants have been discovered for Shunsuke Suzuki.