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Publications (12)100.56 Total impact

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    ABSTRACT: Developmental gene expression is defined through cross-talk between the function of transcription factors and epigenetic status, including histone modification. Although several transcription factors play crucial roles in mammalian sex determination, how epigenetic regulation contributes to this process remains unknown. We observed male-to-female sex reversal in mice lacking the H3K9 demethylase Jmjd1a and found that Jmjd1a regulates expression of the mammalian Y chromosome sex-determining gene Sry. Jmjd1a directly and positively controls Sry expression by regulating H3K9me2 marks. These studies reveal a pivotal role of histone demethylation in mammalian sex determination.
    Science 09/2013; 341(6150):1106-9. · 31.20 Impact Factor
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    ABSTRACT: The generation of induced pluripotent stem cells (iPSCs) provides the opportunity to use patient‐specific somatic cells, which are a valuable source for disease modeling and drug discovery. To promote research involving these cells, it is important to make iPSCs from easily accessible and less invasive tissues, like blood. We have recently reported the efficient generation of human iPSCs from adult fibroblasts using a combination of plasmids encoding OCT3/4, SOX2, KLF4, L‐MYC, LIN28, and shRNA for TP53. We herein report a modified protocol enabling efficient iPSC induction from CD34+ cord blood cells and from peripheral blood isolated from healthy donors using these plasmid vectors. The original plasmid mixture could induce iPSCs; however, the efficiency was low. The addition of EBNA1, an essential factor for episomal amplification of the vectors, by an extra plasmid greatly increased the efficiency of iPSC induction, especially when the induction was performed from αβT cells. This improvement enabled the establishment of blood‐derived iPSCs from seven healthy donors ranging in age from their 20s to their 60s. This induction method will be useful for the derivation of patient‐specific integration‐free iPSCs and would also be applicable to the generation of clinical‐grade iPSCs in the future. STEM CELLS2013;31:458–466
    Stem Cells 01/2013; 31(3). · 7.70 Impact Factor
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    ABSTRACT: We report a simple method, using p53 suppression and nontransforming L-Myc, to generate human induced pluripotent stem cells (iPSCs) with episomal plasmid vectors. We generated human iPSCs from multiple donors, including two putative human leukocyte antigen (HLA)-homozygous donors who match ∼20% of the Japanese population at major HLA loci; most iPSCs are integrated transgene-free. This method may provide iPSCs suitable for autologous and allologous stem-cell therapy in the future.
    Nature Methods 04/2011; 8(5):409-12. · 23.57 Impact Factor
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    ABSTRACT: Methylation of DNA and lysine 9 of histone H3 (H3K9) are well-conserved epigenetic marks for transcriptional silencing. Although H3K9 methylation directs DNA methylation in filamentous fungi and plants, this pathway has not been corroborated in mammals. G9a and GLP/Eu-HMTase1 are two-related mammalian lysine methyltransferases and a G9a/GLP heteromeric complex regulates H3K9 methylation of euchromatin. To elucidate the function of G9a/GLP-mediated H3K9 methylation in the regulation of DNA methylation and transcriptional silencing, we characterized ES cells expressing catalytically inactive mutants of G9a and/or GLP. Interestingly, in ES cells expressing a G9a-mutant/GLP complex that does not rescue global H3K9 methylation, G9a/GLP-target genes remain silent. The CpG sites of the promoter regions of these genes were hypermethylated in such mutant ES cells, but hypomethylated in G9a- or GLP-KO ES cells. Treatment with a DNA methyltransferase inhibitor reactivates these G9a/GLP-target genes in ES cells expressing catalytically inactive G9a/GLP proteins, but not the wild-type proteins. This is the first clear evidence that G9a/GLP suppresses transcription by independently inducing both H3K9 and DNA methylation.
    The EMBO Journal 10/2008; 27(20):2681-90. · 9.82 Impact Factor
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    ABSTRACT: A novel cDNA-encoding polypeptide of 545 amino acid residues was identified from a mouse testis cDNA library. The transcript of this gene, p59(scr), was predominantly expressed in the testis and was developmentally regulated during spermatogenesis. The encoded protein was expressed in spermatocytes and round spermatids within seminiferous tubules of the adult testis. Using an adult-mouse model of experimental unilateral cryptorchidism, it was observed that the expression of the p59(scr) mRNA was reduced in the cryptorchid testes in association with destruction of spermatogenesis. In vitro heat stress experiment further demonstrated that p59(scr) mRNA was more sensitive to heat stress than the other mRNA species, such as germ-cell-specific meiosis-activating kinase (mak) gene and a housekeeping beta-actin gene. Our results suggest that this novel p59(scr) gene is involved in spermatogenesis and may play an important role in development of testicular germ cells.
    Biochemical and Biophysical Research Communications 05/2002; 292(4):992-8. · 2.28 Impact Factor
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    Makoto Senoo, Yasuko Matsumura, Sonoko Habu
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    ABSTRACT: Tumor suppressor p53 has been shown to repress expression of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen and a key mediator of tumor angiogenesis. The p63 gene, recently identified as a p53-relative, encodes multiple isoforms with structural and functional similarities and differences from p53. In this study, we show the evidence that the two major isoforms of the p63 gene, TAp63gamma (p51A) and dNp63alpha (p73L), represses and upregulates VEGF expression, respectively, on transcription and protein levels. Transient transfection assays show that a hypoxia-inducible factor (HIF) 1 binding site within the VEGF promoter region is responsible for both upregulation and repression by dNp63alpha and by TAp63gamma, respectively, of the VEGF promoter activity. We also show that TAp63gamma targets HIF1alpha for promoting proteasomal degradation but that dNp63alpha targets HIF1alpha for stabilization. Mammalian two-hybrid assays show that HIF1alpha-dependent transcription is repressed by TAp63gamma as well as by p53, whereas it is upregulated by dNp63alpha in collaboration with a transcription coactivator p300. Our data also show that dNp63alpha acts as a dominant-negative reagent toward both p53- and TAp63gamma-mediated degradation of HIF1alpha and repression of HIF1alpha-dependent transcription. These results suggest that p63 is involved in the regulation of the VEGF gene expression and that modulation of VEGF expression by TAp63gamma and dNp63alpha is closely correlated with their distinct roles on the regulation of HIF1alpha stability.
    Oncogene 05/2002; 21(16):2455-65. · 8.56 Impact Factor
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    ABSTRACT: Tumor suppressor p53 has been shown to transactivate epidermal growth factor receptor (EGFR) expression through binding to a putative p53 responsive element in the EGFR promoter between nucleotides -265 and -239 (EGFRp53RE). Isotypes of p63 gene products, recently identified as p53 relatives, have a similar function to transactivate several p53 target gene promoters. However, our results indicate that TAp63gamma has a very low ability to bind to the EGFRp53RE and surprisingly represses both basal EGFR promoter activity and endogenous EGFR expression. Transient transfection assays show that the EGFR promoter region between -348 and -293, containing two Sp1 sites, is crucial for the repression of the EGFR expression by TAp63gamma. Mutations in these Sp1 sites in the reporter constructs result in loss of the TAp63gamma repression effect. We further show that TAp63gamma directly interacts with Sp1 by immunoprecipitation analysis and that TAp63gamma impairs Sp1 binding to the target DNA site in electrophoretic mobility shift assays. These results suggest that TAp63gamma is involved in the regulation of the EGFR gene expression through interactions with basal transcription factors.
    Journal of Biological Chemistry 12/2001; 276(45):41717-24. · 4.65 Impact Factor
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    ABSTRACT: We have generated mutant mice in which TCR beta chain enhancer (E(beta)) was replaced with the TCR alpha chain enhancer (E(alpha)). Using this mouse model, we analyzed (i) recombination status of the TCR beta chain genes after functional V(D)J rearrangements occurred in the first allele during double-negative (DN)-to-double-positive (DP) transition and (ii) involvement of E(beta) for the expression of rearranged TCR beta chain genes. Our data show that E(alpha) substituted for E(beta) function to express a similar extent of TCR beta chains exactly at the same time as did E(beta) (CD25+CD44- DN stage), although the proportion of TCR beta+ cells at this stage was low in mutant mice. At the DP stage, germline transcription and histone acetylation of D(beta)-J(beta) loci were detectable at a high degree in both mutant and wild-type mice. However, DP cells in mutant mice retained the germline D(beta)-J(beta) configuration at a higher frequency than that of wild-type mice, whereas both DP cells expressed TCR beta chains to a similar extent. These data suggest that chromatin opening has a limited impact on D(beta)-to-J(beta) recombination at the DP stage and that E(alpha) is functionally equivalent to E(beta) in promoting expression of functionally rearranged TCR beta chain genes through DN-to-DP transition.
    International Immunology 12/2001; 13(11):1405-14. · 3.14 Impact Factor
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    M Senoo, Y Matsumura, S Habu
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    ABSTRACT: The p51/p73L/p63/p40 gene, recently identified as a p53 homolog, encodes two major isoforms, p51A and p73L, which are suggested to have similar functions synonymous with p53 and dominant-negative activity toward both p53 and p51A, respectively. We have cloned a high affinity genomic fragment bound to p51A that was assigned to be a novel retrovirus long terminal repeat. Strikingly, this fragment was found to bind to both p53 and p73L with similar affinity to p51A. Additional demonstration with known p53 response elements suggested that DNA-binding profiles of p51A and p73L were very similar but were distinct from that of p53. Consistent with this novel finding, transient cotransfection experiments in mammalian cells suggested that p73L, when it was expressed at a low level, selectively suppressed p53-dependent transactivation of p21-luc and mdm2-luc but not of cyclinG-luc and bax-luc reporters. These data raise the possibility that p73L differentially modulates the p53 function according to the distinct DNA-binding affinity between these two proteins.
    Biochemical and Biophysical Research Communications 09/2001; 286(3):628-34. · 2.28 Impact Factor
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    ABSTRACT: We have recently identified a second p53 -related p73L gene, also referred to as p63 / p51 / p40 / KET gene, which encodes the 2 major isoforms p73L and p51 resulting from different exon usage at their amino terminal regions. Although p73L and p51 are suspected to play oncogenic and tumour suppressive roles in mammalian cells, respectively, no evidence of linkage between the expression of these isoforms and human cancers has been reported so far. In this study, we first investigated the expression profile of p51 and p73L in various human tumour cell lines and found that a novel isoform, termed DeltaNp73L, was predominantly expressed in squamous cell carcinomas. The expression profile of DeltaNp73L/p73L/p51 in primary human skin cancer specimens showed that the expression of p51 was frequently lost (62%) but was detected in all normal skin samples. In p51-expressing skin cancers, DeltaNp73L expression was associated at a high frequency (75%) though it was not detected in normal skin tissues. Transient co-transfection data indicate the possibility that DeltaNp73L can inhibit p53-, and more preferentially, p51-mediated transactivation. These data suggest that the loss of expression of p51 and/or the expression of DeltaNp73L might contribute to the pathogenesis of human squamous cell carcinomas.
    British Journal of Cancer 06/2001; 84(9):1235-41. · 5.08 Impact Factor
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    M. Senoo, Y. Matsumura, S. Habu
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    ABSTRACT: The p51/p73L/p63/p40 gene, recently identified as a p53 homolog, encodes two major isoforms, p51A and p73L, which are suggested to have similar functions synonymous with p53 and dominant-negative activity toward both p53 and p51A, respectively. We have cloned a high affinity genomic fragment bound to p51A that was assigned to be a novel retrovirus long terminal repeat. Strikingly, this fragment was found to bind to both p53 and p73L with similar affinity to p51A. Additional demonstration with known p53 response elements suggested that DNA-binding profiles of p51A and p73L were very similar but were distinct from that of p53. Consistent with this novel finding, transient cotransfection experiments in mammalian cells suggested that p73L, when it was expressed at a low level, selectively suppressed p53-dependent transactivation of p21-luc and mdm2-luc but not of cyclinG-luc and bax-luc reporters. These data raise the possibility that p73L differentially modulates the p53 function according to the distinct DNA-binding affinity between these two proteins.
    Biochemical and Biophysical Research Communications 01/2001; 286(3). · 2.28 Impact Factor
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    ABSTRACT: We have generated mutant mice in which TCR β chain enhancer (Eβ) was replaced with the TCR α chain enhancer (Eα). Using this mouse model, we analyzed (i) recombination status of the TCR β chain genes after functional V(D)J rearrangements occurred in the first allele during double- negative (DN)-to-double-positive (DP) transition and (ii) involvement of Eβ for the expression of rearranged TCR β chain genes. Our data show that Eα substituted for Eβ function to express a similar extent of TCR β chains exactly at the same time as did Eβ (CD25CD44- DN stage), although the proportion of TCR β cells at this stage was low in mutant mice. At the DP stage, germline transcription and histone acetylation of Dβ-Jβ loci were detectable at a high degree in both mutant and wild-type mice. However, DP cells in mutant mice retained the germline Dβ-Jβ configuration at a higher frequency than that of wild-type mice, whereas both DP cells expressed TCR β chains to a similar extent. These data suggest that chromatin opening has a limited impact on Dβ-to-Jβ recombination at the DP stage and that Eα is functionally equivalent to Eβ in promoting expression of functionally rearranged TCR β chain genes through DN-to-DP transition.