Congenital human cytomegalovirus (HCMV) infection causes sensorineural hearing loss (SNHL) and other neurological disorders, although the neuropathogenesis of HCMV infection is not well understood. Here, we show that the expression of... more
Congenital human cytomegalovirus (HCMV) infection causes sensorineural hearing loss (SNHL) and other neurological disorders, although the neuropathogenesis of HCMV infection is not well understood. Here, we show that the expression of SLITRK6, one of causative genes for hereditary SNHL, was robustly downregulated by HCMV infection in cultured neural cells. We also show that HCMV-encoded immediate-early 2 (IE2) proteins mediate this downregulation and their carboxy-terminal region, especially amino acid residue Gln(548), has a critical role. These findings suggest that the downregulation of SLITRK6 expression by IE2 may have a role in HCMV-induced SNHL and other neurological disorders.
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The adrenocortical cells have been shown to produce various inflammatory cytokines such as TNFα and IL-6, which could modulate steroidogenesis. However, the role of inflammatory cytokines in aldosterone-producing adenomas (APAs) is not... more
The adrenocortical cells have been shown to produce various inflammatory cytokines such as TNFα and IL-6, which could modulate steroidogenesis. However, the role of inflammatory cytokines in aldosterone-producing adenomas (APAs) is not fully understood. In the present study, we examined the relationships between mRNA expression levels of the inflammation-related genes and somatic mutations in APA tissues. We evaluated mRNA expression levels of TNFA, IL6, and NFKB1 in APA tissues obtained from 44 Japanese APA patients. We revealed that mRNA expression patterns of the inflammation-related genes depended on a KCNJ5 somatic mutation. In addition, we showed that mRNA expression levels of the inflammation-related genes correlated with those of the steroidogenic enzyme CYP11B1 in the patients with APAs. The present study documented for the first time the expression of inflammation-related genes in APAs and the correlation of their expression levels with the KCNJ5 mutation status and mRNA expression levels of steroidogenic enzymes, indicating the pathophysiological relevance of inflammation-related genes in APAs.
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We report the case of an 11-year-old girl with ulcerative colitis refractory to conventional therapy, who was subsequently treated successfully with repeated fecal microbiota transplantation (FMT). The patient was steroid dependent... more
We report the case of an 11-year-old girl with ulcerative colitis refractory to conventional therapy, who was subsequently treated successfully with repeated fecal microbiota transplantation (FMT). The patient was steroid dependent despite several infliximab treatments, and colectomy was proposed to improve quality of life. After repeated FMT, she was able to maintain remission with on minimal dose of steroid. Although her fecal microbiota was dysbiotic before FMT, it was restored to a similar pattern as the donor after repeated FMT.
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This report describes androgenetic/biparental mosaicism in a 4-year-old Japanese girl with Beckwith-Wiedemann syndrome (BWS)-like and paternal uniparental disomy 14 (upd(14)pat)-like phenotypes. We performed methylation analysis for 18... more
This report describes androgenetic/biparental mosaicism in a 4-year-old Japanese girl with Beckwith-Wiedemann syndrome (BWS)-like and paternal uniparental disomy 14 (upd(14)pat)-like phenotypes. We performed methylation analysis for 18 differentially methylated regions on various chromosomes, genome-wide microsatellite analysis for a total of 90 loci and expression analysis of SNRPN in leukocytes. Consequently, she was found to have an androgenetic 46,XX cell lineage and a normal 46,XX cell lineage, with the frequency of the androgenetic cells being roughly calculated as 91% in leukocytes, 70% in tongue tissues and 79% in tonsil tissues. It is likely that, after a normal fertilization between an ovum and a sperm, the paternally derived pronucleus alone, but not the maternally derived pronucleus, underwent a mitotic division, resulting both in the generation of the androgenetic cell lineage by endoreplication of one blastomere containing a paternally derived pronucleus and in the formation of the normal cell lineage by union of paternally and maternally derived pronuclei. It appears that the extent of overall (epi)genetic aberrations exceeded the threshold level for the development of BWS-like and upd(14)pat-like phenotypes, but not for the occurrence of other imprinting disorders or recessive Mendelian disorders.
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Upon shift-up in temperature, mouse tsFS20 mutant cells with thermolabile ubiquitin-activating enzyme E1 immediately stopped DNA replication and showed cell cycle arrest in S-phase. In contrast, when the cells were permeabilized with... more
Upon shift-up in temperature, mouse tsFS20 mutant cells with thermolabile ubiquitin-activating enzyme E1 immediately stopped DNA replication and showed cell cycle arrest in S-phase. In contrast, when the cells were permeabilized with lysolecithin after culture at the nonpermissive temperature, they exhibited a normal level of replicative DNA synthesis in vitro. In agreement with this, intracellular pools of deoxyribonucleoside triphosphates were significantly reduced in the cells cultured at the nonpermissive temperature. Even under the permissive conditions, tsFS20 cells were more sensitive to hydroxyurea and alkylating agents, and induced less mutation than the wild-type cells. These results suggest that the ubiquitin system affects DNA replication and repair.
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Some immortal human cell lines lack telomerase activity. These cell lines were found to contain small dispersed DNA hybridizing to TTAGGG repeats. Such DNA was located in their cytoplasm and nuclei. Normal human fibroblasts or... more
Some immortal human cell lines lack telomerase activity. These cell lines were found to contain small dispersed DNA hybridizing to TTAGGG repeats. Such DNA was located in their cytoplasm and nuclei. Normal human fibroblasts or telomerase-positive cell lines did not contain such DNA. Upon cloning and sequencing, it was shown to consist of TTAGGG repeats. When electrophoresed on neutral and alkaline agarose gels, it behaved as double-stranded and linear DNA. These results suggest that telomeric DNA is released from chromosomes in association with maintenance of telomeres in telomerase-negative cell lines.
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Whole-genome and -exome resequencing using next-generation sequencers is a powerful approach for identifying genomic variations that are associated with diseases. However, systematic strategies for prioritizing causative variants from... more
Whole-genome and -exome resequencing using next-generation sequencers is a powerful approach for identifying genomic variations that are associated with diseases. However, systematic strategies for prioritizing causative variants from many candidates to explain the disease phenotype are still far from being established, because the population-specific frequency spectrum of genetic variation has not been characterized. Here, we have collected exomic genetic variation from 1208 Japanese individuals through a collaborative effort, and aggregated the data into a prevailing catalog. In total, we identified 156 622 previously unreported variants. The allele frequencies for the majority (88.8%) were lower than 0.5% in allele frequency and predicted to be functionally deleterious. In addition, we have constructed a Japanese-specific major allele reference genome by which the number of unique mapping of the short reads in our data has increased 0.045% on average. Our results illustrate the i...
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Previously, we found that C57BL/6J (B6) mice are more prone to develop obesity than PWK mice. In addition, we analyzed reciprocal crosses between these mice and found that (PWK × B6) F1 mice, which have B6 fathers, are more likely to... more
Previously, we found that C57BL/6J (B6) mice are more prone to develop obesity than PWK mice. In addition, we analyzed reciprocal crosses between these mice and found that (PWK × B6) F1 mice, which have B6 fathers, are more likely to develop dietary obesity than (B6 × PWK) F1 mice, which have B6 mothers. These results suggested that diet-induced obesity is paternally transmitted. In this study, we performed transcriptome analysis of adipose tissues of B6, PWK, (PWK × B6) F1, and (B6 × PWK) F1 mice using next-generation sequencing. We found that paternal transmission of diet-induced obesity was correlated with genes involved in adipose tissue inflammation, metal ion transport, and cilia. Furthermore, we analyzed the imprinted genes expressed in white adipose tissue (WAT) and obesity. Expression of paternally expressed imprinted genes (PEGs) was negatively correlated with body weight, whereas expression of maternally expressed imprinted genes (MEGs) was positively correlated. In the o...
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Aberrant DNA methylation is associated with a range of human disorders. To identify differences in DNA methylation of gene promoters between placentas of low-birth-weight (LBW) and normal-birth-weight (NBW) infants, we screened 8091 genes... more
Aberrant DNA methylation is associated with a range of human disorders. To identify differences in DNA methylation of gene promoters between placentas of low-birth-weight (LBW) and normal-birth-weight (NBW) infants, we screened 8091 genes for aberrant methylation in placentas using microarray-based integrated analysis of methylation by isoschizomers (MIAMI). Seven candidate genes for hypomethylation in the placentas of LBW infants were selected. Among these candidates, COBRA analyses suggested that the HUS1B gene was hypomethylated in some of the placentas. Quantitative methylation analyses by bisulfite-pyrosequencing indicated that the promoter region of the gene was hypomethylated in three of the 86 placentas analyzed. The HUS1B promoter was highly methylated in two cell lines derived from trophoblastic cells. Gene expression increased when the promoter was demethylated by 5Aza-dC treatment. This suggests that hypomethylation of HUS1B alters gene expression in the placenta and that this dysregulated gene expression may contribute to the pathogenesis of LBW by affecting placental functions involved in fetal growth.
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We aimed to improve the efficiency of isolating endometrial epithelial and stromal cells (EMECs and EMSCs) from the human endometrium. We revealed by immunohistochemical staining that the large tissue fragments remaining after collagenase... more
We aimed to improve the efficiency of isolating endometrial epithelial and stromal cells (EMECs and EMSCs) from the human endometrium. We revealed by immunohistochemical staining that the large tissue fragments remaining after collagenase treatment, which are usually discarded after the first filtration in the conventional protocol, consisted of glandular epithelial and stromal cells. Therefore, we established protease treatment and cell suspension conditions to dissociate single cells from the tissue fragments and isolated epithelial (EPCAM-positive) and stromal (CD13-positive) cells by fluorescence-activated cell sorting. Four independent experiments showed that, on average, 1.2 × 10(6) of EMECs and 2.8 × 10(6) EMSCs were isolated from one hysterectomy specimen. We confirmed that the isolated cells presented transcriptomic features highly similar to those of epithelial and stromal cells obtained by the conventional method. Our improved protocol facilitates future studies to better...
Research Interests: Zoology, Flow Cytometry, Immunohistochemistry, Cell separation, Transcriptome, and 13 moreCell Differentiation, Humans, Female, Young Adult, Menstrual Cycle, Middle Aged, Epithelial cells, Adult, Stromal Cells, Veterinary Sciences, Endometrium, Gene expression profiling, and Paediatrics and reproductive medicine
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This study aimed to clarify the genetic and epigenetic features of recurrent hydatidiform mole (RHM) in Japanese patients. Four Japanese isolated RHM cases were analyzed using whole-exome sequencing. Villi from RHMs were collected by... more
This study aimed to clarify the genetic and epigenetic features of recurrent hydatidiform mole (RHM) in Japanese patients. Four Japanese isolated RHM cases were analyzed using whole-exome sequencing. Villi from RHMs were collected by laser microdissection for genotyping and DNA methylation assay of differentially methylated regions (DMRs). Single nucleotide polymorphisms of PEG3 and H19 DMRs were used to confirm the parental origin of the variants. A novel homozygous nonsense mutation in NLRP7 (c.584G>A; p.W195X) was identified in 1 patient. Genotyping of one of her molar tissue revealed that it was biparental but not androgenetic in origin. Despite the fact that the RHM is biparental, maternally methylated DMRs of PEG3, SNRPN and PEG10 showed complete loss of DNA methylation. A paternally methylated DMR of H19 retained normal methylation. This is the first Japanese case of RHM with a novel homozygous nonsense NLRP7 mutation and a specific loss of maternal DNA methylation of DMRs...
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ABSTRACT
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Autophagy is activated by environment unfavorable for survival and requires Atg9a protein. Mice heterozygous for p57(Kip2), devoid of the imprinted paternal allele (p57(Kip2+/-)), are known to develop hypertension during pregnancy. To... more
Autophagy is activated by environment unfavorable for survival and requires Atg9a protein. Mice heterozygous for p57(Kip2), devoid of the imprinted paternal allele (p57(Kip2+/-)), are known to develop hypertension during pregnancy. To determine whether fetal Atg9a is involved in the intrauterine survival and growth of fetal mice, this study was performed on Atg9a heterozygous (Atg9a(+/-)) pregnant mice with and without p57(Kip2+/-). The pregnant mice heterozygous for both knockout alleles of Atg9a and p57(Kip2) (Atg9a(+/-)/p57(Kip2+/-)), but not those heterozygous for Atg9a alone, developed hypertension during pregnancy. Placental expression of Atg9a mRNA was significantly decreased in the Atg9a(-/-) mice compared to Atg9a(+/-) or Atg9a(+/+) mice. The Atg9a(-/-) fetal mice exhibited significantly retarded growth and were more likely to die in utero compared to Atg9a(+/+) and Atg9a(+/-) fetal mice. Growth retardation was observed in the presence of maternal hypertension in Atg9a(-/-)...
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ABSTRACT
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Parental allele-specific expression of imprinted genes is mediated by imprinting control regions (ICRs) that are constitutively marked by DNA methylation imprints on the maternal or paternal allele. Mono-allelic DNA methylation is... more
Parental allele-specific expression of imprinted genes is mediated by imprinting control regions (ICRs) that are constitutively marked by DNA methylation imprints on the maternal or paternal allele. Mono-allelic DNA methylation is strictly required for the process of imprinting and has to be faithfully maintained during the entire life-span. While the regulation of DNA methylation itself is well understood, the mechanisms whereby the opposite allele remains unmethylated are unclear. Here, we show that in the mouse, at maternally methylated ICRs, the paternal allele, which is constitutively associated with H3K4me2/3, is marked by default by H3K27me3 when these ICRs are transcriptionally inactive, leading to the formation of a bivalent chromatin signature. Our data suggest that at ICRs, chromatin bivalency has a protective role by ensuring that DNA on the paternal allele remains unmethylated and protected against spurious and unscheduled gene expression. Moreover, they provide the pro...
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TRAPPC9 is a gene that has been implicated in autosomal recessive intellectual disability (ID). Its protein product, NIBP, is an activator of the NF-κb transcription factor and may be involved in cellular trafficking. Many ID genes have... more
TRAPPC9 is a gene that has been implicated in autosomal recessive intellectual disability (ID). Its protein product, NIBP, is an activator of the NF-κb transcription factor and may be involved in cellular trafficking. Many ID genes have been implicated in autism and we hypothesized that TRAPPC9 mutations may contribute to the autism phenotype as well. Unique CNVs overlapping TRAPPC9 have been identified in 7 individuals with varying neurodevelopmental phenotypes. Four of these CNVs are maternally inherited, one is paternally inherited, and two are of unknown inheritance. Two are duplications, five are deletions, and all of them overlap exons of the gene. We have validated two of these CNVs, a deletion and duplication, using qPCR. TRAPPC9 displays a recessive inheritance pattern in individuals with ID, however, it is partially paternally imprinted in mouse brain. Two other genes at the same locus, Kcnk9 and Eif2c2, are also imprinted in mouse brain. Our group has confirmed preferenti...
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Insulators are cis-elements that control the direction of enhancer and silencer activities (enhancer-blocking) and protect genes from silencing by heterochromatinization (barrier activity). Understanding insulators is critical to... more
Insulators are cis-elements that control the direction of enhancer and silencer activities (enhancer-blocking) and protect genes from silencing by heterochromatinization (barrier activity). Understanding insulators is critical to elucidate gene regulatory mechanisms at chromosomal domain levels. Here, we focused on a genomic region upstream of the mouse Ccnb1ip1 (cyclin B1 interacting protein 1) gene that was methylated in E9.5 embryos of the C57BL/6 strain, but unmethylated in those of the 129X1/SvJ and JF1/Ms strains. We hypothesized the existence of an insulator-type element that prevents the spread of DNA methylation within the 1.8 kbp segment, and actually identified a 242-bp and a 185-bp fragments that were located adjacent to each other and showed insulator and enhancer activities, respectively, in reporter assays. We designated these genomic regions as the Ccnb1ip1 insulator and the Ccnb1ip1 enhancer. The Ccnb1ip1 insulator showed enhancer-blocking activity in the luciferase...
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The pathophysiology of aldosterone-producing adenomas (APA) has been investigated intensively through genetic and genomic approaches. However, the role of epigenetics in APA is not fully understood. In the present study, we explored the... more
The pathophysiology of aldosterone-producing adenomas (APA) has been investigated intensively through genetic and genomic approaches. However, the role of epigenetics in APA is not fully understood. In the present study, we explored the relationship between gene expression and DNA methylation status in APA. We conducted an integrated analysis of transcriptome and methylome data of paired APA-adjacent adrenal gland (AAG) samples from the same patient. The adrenal specimens were obtained from seven Japanese patients with APA who underwent adrenalectomy. Gene expression and genome-wide CpG methylation profiles were obtained from RNA and DNA samples that were extracted from those seven paired tissues. Methylome analysis showed global CpG hypomethylation in APA relative to AAG. The integration of gene expression and methylation status showed that 34 genes were up-regulated with CpG hypomethylation in APA. Of these, three genes (CYP11B2, MC2R, and HPX) may be related to aldosterone produc...
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ABSTRACT Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because... more
ABSTRACT Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
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Y chromosomal azoospermia factor (AZF) regions AZFa, AZFb and AZFc represent hotspots for copy number variations (CNVs) in the human genome; yet the number of reports of AZFa-linked duplications remains limited. Nonallelic homologous... more
Y chromosomal azoospermia factor (AZF) regions AZFa, AZFb and AZFc represent hotspots for copy number variations (CNVs) in the human genome; yet the number of reports of AZFa-linked duplications remains limited. Nonallelic homologous recombination has been proposed as the underlying mechanism of CNVs in AZF regions. In this study, we identified a hitherto unreported microduplication in the AZFa region in a Japanese male individual. The 629,812-bp duplication contained 22 of 46 exons of USP9Y, encoding the putative fine tuner of spermatogenesis, together with all exons of 3 other genes/pseudogenes. The breakpoints of the duplication resided in the DNA/TcMar-Tigger repeat and nonrepeat sequences, respectively, and were associated with a 2-bp microhomology, but not with short nucleotide stretches. The breakpoint-flanking regions were not enriched with GC content, palindromes, or noncanonical DNA structures. Semen analysis of the individual revealed a normal sperm concentration and mild...
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Research Interests: Japan, Humans, Chronic Disease, Female, Male, and 4 morePedigree, Leg Ulcer, Clinical Sciences, and Middle Aged
Autophagy has not been studied extensively in the human placenta. This study was performed to determine whether autophagy is increased in the placentas of women with hypertensive disorders in pregnancy compared to normotensive... more
Autophagy has not been studied extensively in the human placenta. This study was performed to determine whether autophagy is increased in the placentas of women with hypertensive disorders in pregnancy compared to normotensive pregnancies. LC3-II and p62 protein expression were examined by quantitative Western blotting analysis in 40 placentas from women not experiencing labor pains. The 40 placentas were from 13, 8, and 19 women with preeclampsia, gestational hypertension, and normal pregnancy, respectively. Hypertensive disorders in pregnancy included preeclampsia and gestational hypertension. LC3-II expression was significantly increased, while that of p62 was significantly reduced in 21 placentas of women with hypertensive disorders compared to those with normal blood pressure irrespective of the presence or absence of fetal growth restriction (FGR). LC3-II expression was also significantly increased in 13 placentas of women with preeclampsia irrespective of the presence or abse...
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The juvenile form of GM1 gangliosidosis lacks specific physical findings and thus is often a diagnostic challenge for clinicians. T2 hypodensity in the globus pallidus is a characteristic radiographic sign of neurodegeneration with iron... more
The juvenile form of GM1 gangliosidosis lacks specific physical findings and thus is often a diagnostic challenge for clinicians. T2 hypodensity in the globus pallidus is a characteristic radiographic sign of neurodegeneration with iron accumulation in the brain that is observed in GM1 gangliosidosis, but the exact timing when this radiographic sign becomes apparent remains to be elucidated. Two male siblings had normal development until 2 years of age and then developed psychomotor regression with dystonia. Their neuroimaging studies indicated progressive global cerebral atrophy. Exome sequencing identified compound heterozygous missense mutations in GLB1, leading to a diagnosis of GM1 gangliosidosis. A retrospective review of neuroimaging studies revealed that the two patients had strikingly similar clinical courses and radiographic progressions with cortical atrophy that preceded the T2 hypointensity in the globus pallidus. Paramagnetic signals in the globus pallidus become appar...
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Maternal uniparental disomy 14 (UPD(14)mat) and related (epi)genetic aberrations affecting the 14q32.2 imprinted region result in a clinically recognizable condition which is recently referred to as Temple syndrome (TS). Phenotypic... more
Maternal uniparental disomy 14 (UPD(14)mat) and related (epi)genetic aberrations affecting the 14q32.2 imprinted region result in a clinically recognizable condition which is recently referred to as Temple syndrome (TS). Phenotypic features in TS include pre- and post-natal growth failure, prominent forehead, and feeding difficulties that are also found in Silver-Russell syndrome (SRS). Thus, we examined the relevance of UPD(14)mat and related (epi)genetic aberrations to the development of SRS in 85 Japanese patients who satisfied the SRS diagnostic criteria proposed by Netchine et al and had neither epimutation of the H19-DMR nor maternal uniparental disomy 7. Pyrosequencing identified hypomethylation of the DLK1-MEG3 intergenic differentially methylated region (IG-DMR) and the MEG3-DMR in two cases. In both cases, microsatellite analysis showed biparental transmission of the homologs of chromosome 14, with no evidence for somatic mosaicism with full or segmental maternal isodisomy...
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Expression of imprinted genes is regulated by DNA methylation of differentially methylated regions (DMRs). Beckwith-Wiedemann syndrome is an imprinting disorder caused by epimutations of DMRs at 11p15.5. To date, multiple methylation... more
Expression of imprinted genes is regulated by DNA methylation of differentially methylated regions (DMRs). Beckwith-Wiedemann syndrome is an imprinting disorder caused by epimutations of DMRs at 11p15.5. To date, multiple methylation defects have been reported in Beckwith-Wiedemann syndrome patients with epimutations; however, limited numbers of DMRs have been analyzed. The susceptibility of DMRs to aberrant methylation, alteration of gene expression due to aberrant methylation, and causative factors for multiple methylation defects remain undetermined. Comprehensive methylation analysis with two quantitative methods, matrix-assisted laser desorption/ionization mass spectrometry and bisulfite pyrosequencing, was conducted across 29 DMRs in 54 Beckwith-Wiedemann syndrome patients with epimutations. Allelic expressions of three genes with aberrant methylation were analyzed. All DMRs with aberrant methylation were sequenced. Thirty-four percent of KvDMR1-loss of methylation patients an...
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Autoimmune thyroid disease (AITD), including Graves'disease (GD) and Hashimoto's thyroiditis (HT), is caused by immune response to self-thyroid antigens, and affects up to 2-5% of the general population. Twin studies and familial... more
Autoimmune thyroid disease (AITD), including Graves'disease (GD) and Hashimoto's thyroiditis (HT), is caused by immune response to self-thyroid antigens, and affects up to 2-5% of the general population. Twin studies and familial aggregation have clearly indicated the involvement of genetic factors with AITD in addition to environmental factors. Known AITD-susceptibility genes are classified into three categories: HLA genes, non-HLA immune-related genes, and thyroid-specific genes. A comprehensive catalogue of AITD-susceptibility genes with major effects will facilitates elucidating the molecular mechanisms underlying the initiation of AITD. Genome-wide association studies conducted for autoimmune diseases in the last few years have identified a significant number of novel loci contributing disease risk. In this review, we describe the current status of genome-wide association studies for GD and the recent advances in the functional characterization of ZFAT, an AITD-related ...
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Information about human genetic variation collected by the HapMap project and recent advances in high-throughput genotyping have made genome-wide association studies (GWAS) technically feasible. In the past two years, through GWAS using... more
Information about human genetic variation collected by the HapMap project and recent advances in high-throughput genotyping have made genome-wide association studies (GWAS) technically feasible. In the past two years, through GWAS using commercially available SNP-typing platforms, numerous loci contributing to disease risk have been identified for common diseases including rheumatoid arthritis and systemic lupus erythematosus. From such successful studies, human geneticists have gained not only broad consensuses in methodological and technical issues, but also clear recognition about the current limitations in the common SNP-based GWAS strategy. Large-scale projects are ongoing to comprehensively catalogue genome structural variants and rare SNPs in multiple human populations. Such a deeper catalogue of genetic variation will accelerate the identification of genetic risk variants associated with common diseases.
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Although DNA methylation is considered to play an important role during myogenic differentiation, chronological alterations in DNA methylation and gene expression patterns in this process have been poorly understood. Using the Infinium... more
Although DNA methylation is considered to play an important role during myogenic differentiation, chronological alterations in DNA methylation and gene expression patterns in this process have been poorly understood. Using the Infinium HumanMethylation450 BeadChip array, we obtained a chronological profile of the genome-wide DNA methylation status in a human myoblast differentiation model, where myoblasts were cultured in low-serum medium to stimulate myogenic differentiation. As the differentiation of the myoblasts proceeded, their global DNA methylation level increased and their methylation patterns became more distinct from those of mesenchymal stem cells. Gene ontology analysis revealed that genes whose promoter region was hypermethylated upon myoblast differentiation were highly significantly enriched with muscle-related terms such as 'muscle contraction' and 'muscle system process'. Sequence motif analysis identified 8-bp motifs somewhat similar to the binding ...
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Immortal SVts8 cells that express thermolabile SV40 T antigen exhibit a senescence-like phenomenon upon inactivation of the T antigen. By using a cDNA subtractive hybridization technique, RAB27B, a member of the RAB GTPase family, was... more
Immortal SVts8 cells that express thermolabile SV40 T antigen exhibit a senescence-like phenomenon upon inactivation of the T antigen. By using a cDNA subtractive hybridization technique, RAB27B, a member of the RAB GTPase family, was found to be up-regulated in senescent SVts8 cells. The up-regulation of RAB27B depends on the p53 gene. Enhanced expression was also observed in replicative senescence in normal human fibroblasts.
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To clarify the molecular basis of hypogonadotropic hypogonadism (HH). Genome-wide copy number analysis by array-based comparative genomic hybridization and systematic mutation screening of 29 known causative genes by next-generation... more
To clarify the molecular basis of hypogonadotropic hypogonadism (HH). Genome-wide copy number analysis by array-based comparative genomic hybridization and systematic mutation screening of 29 known causative genes by next-generation sequencing, followed by in silico functional assessment and messenger RNA/DNA analyses of the mutants/variants. Research institute. Fifty-eight patients with isolated HH (IHH), combined pituitary hormone deficiency (CPHD), and syndromic HH. None. Frequency and character of molecular abnormalities. Pathogenic defects were identified in 14 patients with various types of HH, although oligogenicity was not evident in this patient group. As rare abnormalities, we identified a submicroscopic deletion involving FGFR1 and an SOX3 polyalanine deletion in patients with IHH, and a WDR11 splice site mutation in a patient with CPHD. No disease-associated polymorphism was detected in the 58 patients. The present study provides further evidence that mutations and delet...
Research Interests: Membrane Proteins, Adolescent, Humans, Child, Genetic Testing, and 15 moreMutation, Fertility and Sterility, Female, Male, Infant, Gene Dosage, Hypopituitarism, Clinical Sciences, Middle Aged, Late onset hypogonadism, Adult, Comparative Genomic Hybridization, DNA mutational analysis, Child preschool, and hypogonadism
Maintaining a single active X-chromosome by repressing Xist is crucial for embryonic development in mice. Although the Xist activator RNF12/RLIM is present as a maternal factor, maternal Xist (Xm-Xist) is repressed during preimplantation... more
Maintaining a single active X-chromosome by repressing Xist is crucial for embryonic development in mice. Although the Xist activator RNF12/RLIM is present as a maternal factor, maternal Xist (Xm-Xist) is repressed during preimplantation phases to establish imprinted X-chromosome inactivation (XCI). Here we show, using a highly reproducible chromatin immunoprecipitation method that facilitates chromatin analysis of preimplantation embryos, that H3K9me3 is enriched at the Xist promoter region, preventing Xm-Xist activation by RNF12. The high levels of H3K9me3 at the Xist promoter region are lost in embryonic stem (ES) cells, and ES-cloned embryos show RNF12-dependent Xist expression. Moreover, lack of Xm-XCI in the trophectoderm, rather than loss of paternally expressed imprinted genes, is the primary cause of embryonic lethality in 70-80% of parthenogenotes immediately after implantation. This study reveals that H3K9me3 is involved in the imprinting that silences Xm-Xist. Our findin...