研究者詳細 - 洪　実

論文 - 洪　実

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Gene expression changes at metamorphosis induced by thyroid hormone in Xenopus laevis tadpoles

Das Biswajit, Cai Liquan, Carter Mark G., Piao Yu Lan, Sharov Alexei A., Ko Minoru S H, Brown Donald D.

Developmental Biology 291 （ 2 ） 342 - 355 2006年03月

ISSN 0012-1606

Thyroid hormone (TH) controlled gene expression profiles have been studied in the tail, hind limb and brain tissues during TH-induced and spontaneous Xenopus laevis metamorphosis. Amplified cRNA probes mixed with a universal standard were hybridized to a set of 21,807-sense strand 60-mer oligonucleotides on each slide representing the entries in X. laevis UniGene Build 48. Most of the up-regulated genes in hind limb and brain are the same. This reflects in part the fact that the initial response to TH induction in both tissues is cell proliferation. A large number of up-regulated genes in the limb and brain programs encode common components of the cell cycle, DNA and RNA metabolism, transcription and translation. Notch is one of the few genes that is differentially expressed exclusively in the brain in the first 48 h of TH induction studied in these experiments. The TH-induced gene expression changes in the tail are different from the limb and brain programs. Distinct muscle and fibroblast programs were identified in the tail. Dying muscle fibers in tail (marked by active caspase-3) up-regulate a group of genes that include proteolytic enzymes. At the climax of metamorphosis, tail muscle down-regulates more than half of the genes that encode the glycolytic enzymes in the cytoplasm and the tricarboxylic acid pathway and all five complexes of the electron transport system in mitochondria. These changes in gene expression precede the activation of caspase-3. Some of these same energy metabolism-related genes are up-regulated in the limb and brain programs by TH. A prominent feature of the tail fibroblasts is the down-regulation of several collagen and other extra cellular matrix genes and the up-regulation of hydrolytic enzymes that are responsible for dissolving the notochord and resorbing the tail. © 2005 Elsevier Inc. All rights reserved.

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Epigenetics of germ cells, stem cells, and early embryos

Ko Minoru S H, McLaren Anne

Developmental Cell 10 （ 2 ） 161 - 166 2006年02月

ISSN 1534-5807

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Meet our Editor

Ko Minoru S H

Reproductive BioMedicine Online 12 （ 2 ） 143 2006年02月

ISSN 1472-6483

The multifunctional RNA-binding protein La is required for mouse development and for the establishment of embryonic stem cells

Park Jung Min, Kohn Matthew J., Bruinsma Monique W., Vech Claire, Intine Robert V., Fuhrmann Stacy, Grinberg Alex, Mukherjee Ipsita, Love Paul E., Ko Minoru S., DePamphilis Melvin L., Maraia Richard J.

Molecular and Cellular Biology 26 （ 4 ） 1445 - 1451 2006年02月

ISSN 0270-7306

The La protein is a target of autoantibodies in patients suffering from Sjögren's syndrome, systemic lupus erythematosus, and neonatal lupus. Ubiquitous in eukaryotes, La functions as a RNA-binding protein that promotes the maturation of tRNA precursors and other nascent transcripts synthesized by RNA polymerase III as well as other noncoding RNAs. La also associates with a class of mRNAs that encode ribosome subunits and precursors to snoRNAs involved in ribosome biogenesis. Thus, it was surprising that La is dispensable in the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, the organisms from which it has been characterized most extensively. To determine whether La is essential in mammals and if so, at which developmental stage it is required, mice were created with a disrupted La gene, and the offspring from La ^+/- intercrosses were analyzed. La^-/- offspring were detected at the expected frequency among blastocysts prior to implantation, whereas no nullizygotes were detected after implantation, indicating that La is required early in development. Blastocysts derived from La^+/- intercrosses yielded 38 La^+/+ and La^+/- embryonic stem (ES) cell lines but no La^-/- ES cell lines, suggesting that La contributes a critical function toward the establishment or survival of ES cells. Consistent with this, La^-/- blastocyst outgrowths revealed loss of the inner cell mass (ICM). The results indicate that in contrast to the situation in yeasts, La is essential in mammals and is one of a limited number of genes required as early as the development of the ICM.

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High-throughput screen for genes predominantly expressed in the ICM of mouse blastocysts by whole mount in situ hybridization

Yoshikawa Toshiyuki, Piao Yulan, Zhong Jinhui, Matoba Ryo, Carter Mark G., Wang Yuxia, Goldberg Ilya, Ko Minoru S H

Gene Expression Patterns 6 （ 2 ） 213 - 224 2006年01月

ISSN 1567-133X

Mammalian preimplantation embryos provide an excellent opportunity to study temporal and spatial gene expression in whole mount in situ hybridization (WISH). However, large-scale studies are made difficult by the size of the embryos (∼60 μm diameter) and their fragility. We have developed a chamber system that allows parallel processing of embryos without the aid of a microscope. We first selected 91 candidate genes that were transcription factors highly expressed in blastocysts, and more highly expressed in embryonic (ES) than in trophoblast (TS) stem cells. We then used the WISH to identify 48 genes expressed predominantly in the inner cell mass (ICM) and to follow several of these genes in all seven preimplantation stages. The ICM-predominant expressions of these genes suggest their involvement in the pluripotency of embryonic cells. This system provides a useful tool to a systematic genome-scale analysis of preimplantation embryos.

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CisView

Sharov Alexei A., Dudekula Dawood B., Ko Minoru S H

DNA Research 13 （ 3 ） 123 - 134 2006年

ISSN 1340-2838

To facilitate the analysis of gene regulatory regions of the mouse genome, we developed a CisView (http:x//lgsun.grc.nia.nih.gov/cisview), a browser and database of genome-wide potential transcription factor binding sites (TFBSs) that were identified using 134 position-weight matrices and 219 sequence patterns from various sources and were presented with the information about sequence conservation, neighboring genes and their structures, GO annotations, protein domains, DNA repeats and CpG islands. Analysis of the distribution of TFBSs revealed that many TFBSs (N = 145) were over-represented near transcription start sites. We also identified potential cis-regulatory modules (CRMs) defined as clusters of conserved TFBSs in the entire mouse genome. Out of 739 074 CRMs, 157 442 had a significantly higher regulatory potential score than semi-random sequences generated with a 3rd-order Markov process. The CisView browser provides a user-friendly computer environment for studying transcription regulation on a whole-genome scale and can also be used for interpreting microarray experiments and identifying putative targets of transcription factors. © The Author 2006. Kazusa DNA Research Institute.

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Identification of target genes and a unique cis element regulated by IRF-8 in developing macrophages

Tamura Tomohiko, Thotakura Pratima, Tanaka Tetsuya S., Ko Minoru S H, Ozato Keiko

Blood 106 （ 6 ） 1938 - 1947 2005年09月

ISSN 0006-4971

Interferon regulatory factor-8 (IRF-8)/interferon consensus sequence-binding protein (ICSBP) is a transcription factor that controls myeloid-cell development. Microarray gene expression analysis of Irf-8 ^-/- myeloid progenitor cells expressing an IRF-8/estrogen receptor chimera (which differentiate into macrophages after addition of estradiol) was used to identify 69 genes altered by IRF-8 during early differentiation (62 up-regulated and 7 down-regulated). Among them, 4 lysosomal/endosomal enzyme-related genes (cystatin C, cathepsin C, lysozyme, and prosaposin) did not require de novo protein synthesis for induction, suggesting that they were direct targets of IRF-8. We developed a reporter assay system employing a self-inactivating retrovirus and analyzed the cystatin C and cathepsin C promoters. We found that a unique cis element mediates IRF-8-induced activation of both promoters. Similar elements were also found in other IRF-8 target genes with a consensus sequence (GAAANN[N]GGAA) comprising a core IRF-binding motif and an Ets-binding motif; this sequence is similar but distinct from the previously reported Ets/IRF composite element. Chromatin immunoprecipitation assays demonstrated that IRF-8 and the PU.1 Ets transcription factor bind to this element in vivo. Collectively, these data indicate that IRF-8 stimulates transcription of target genes through a novel cis element to specify macrophage differentiation. © 2005 by The American Society of Hematology.

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Identification of Zfp-57 as a downstream molecule of STAT3 and Oct-3/4 in embryonic stem cells

Akagi Tadayuki, Usuda Masayuki, Matsuda Takahiko, Ko Minoru S H, Niwa Hitoshi, Asano Masahide, Koide Hiroshi, Yokota Takashi

Biochemical and Biophysical Research Communications 331 （ 1 ） 23 - 30 2005年05月

ISSN 0006-291X

Embryonic stem (ES) cells are pluripotent cells derived from the inner cell mass of blastocysts. Transcription factor STAT3 is essential for the self-renewal of ES cells. In this study, we searched for downstream molecules of STAT3 in ES cells. Using DNA chip analysis, we obtained zinc finger protein (Zfp)-57. The expression of Zfp-57 was restricted to undifferentiated ES cells and activation of STAT3 led to expression of Zfp-57. We also found that forced expression of a dominant-negative mutant of STAT3 or repression of Oct-3/4 expression led to down-regulation of Zfp-57. Targeted disruption of Zfp-57 resulted in no gross phenotypical defects, including expression of undifferentiated-state-specific genes. These data suggest that Zfp-57 is a downstream molecule of STAT3 and Oct-3/4 in ES cells, although dispensable for their self-renewal. © 2005 Elsevier Inc. All rights reserved.

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A web-based tool for principal component and significance analysis of microarray data

Sharov Alexei A., Dudekula Dawood B., Ko Minoru S H

Bioinformatics 21 （ 10 ） 2548 - 2549 2005年05月

ISSN 1367-4803

Summary: We have developed a program for microarray data analysis, which features the false discovery rate for testing statistical significance and the principal component analysis using the singular value decomposition method for detecting the global trends of gene-expression patterns. Additional features include analysis of variance with multiple methods for error variance adjustment, correction of cross-channel correlation for two-color microarrays, identification of genes specific to each cluster of tissue samples, biplot of tissues and corresponding tissue-specific genes, clustering of genes that are correlated with each principal component (PC), three-dimensional graphics based on virtual reality modeling language and sharing of PC between different experiments. The software also supports parameter adjustment, gene search and graphical output of results. The software is implemented as a web tool and thus the speed of analysis does not depend on the power of a client computer. © The Author 2005. Published by Oxford University Press. All rights reserved.

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Genome-wide assembly and analysis of alternative transcripts in mouse

Sharov Alexei A., Dudekula Dawood B., Ko Minoru S H

Genome Research 15 （ 5 ） 748 - 754 2005年05月

ISSN 1088-9051

To build a mouse gene index with the most comprehensive coverage of alternative transcription/splicing (ATS), we developed an algorithm and a fully automated computational pipeline for transcript assembly from expressed sequences aligned to the genome. We identified 191,946 genomic loci, which included 27,497 protein-coding genes and 11,906 additional gene candidates (e.g., nonprotein-coding, but multiexon). Comparison of the resulting gene index with TIGR, UniGene, DoTS, and ESTGenes databases revealed that it had a greater number of transcripts, a greater average number of exons and introns with proper splicing sites per gene, and longer ORFs. The 27,497 protein-coding genes had 77,138 transcripts, i.e., 2.8 transcripts per gene on average. Close examination of transcripts led to a combinatorial table of 23 types of ATS units, only nine of which were previously described, i.e., 14 types of alternative splicing, seven types of alternative starts, and two types of alternative termination. The 47%, 18%, and 14% of 20,323 multiexon protein-coding genes with proper splice sites had alternative splicings, alternative starts, and alternative terminations, respectively. The gene index with the comprehensive ATS will provide a useful platform for analyzing the nature and mechanism of ATS, as well as for designing the accurate exon-based DNA microarrays. ©2005 by Cold Spring Harbor Laboratory Press.

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Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice

Sakatani Takashi, Kaneda Atsushi, Iacobuzio-Donahue Christine A., Carter Mark G., De Boom Witzel Sten, Okano Hideyuki, Ko Minora S H, Ohlsson Rolf, Longo Dan L., Feinberg Andrew P.

Science 307 （ 5717 ） 1976 - 1978 2005年03月

ISSN 0036-8075

Loss of imprinting (LOI) of the insulin-like growth factor II gene (IGF2) is an epigenetic alteration that results in a modest increase in IGF2 expression, and it is present in the normal colonic mucosa of about 30% of patients with colorectal cancer. To investigate its role in intestinal tumorigenesis, we created a mouse model of Igf2 LOI by crossing female H19 ^+/- mice with male Apc^+/Min mice. Mice with LOI developed twice as many intestinal tumors as did control littermates. Notably, these mice also showed a shift toward a less differentiated normal intestinal epithelium, reflected by an increase in crypt length and increased staining with progenitor cell markers. A similar shift in differentiation was seen in the normal colonic mucosa of humans with LOI. Thus, altered maturation of nonneoplastic tissue may be one mechanism by which epigenetic changes affect cancer risk.

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Mouse ovary developmental RNA and protein markers from gene expression profiling

Herrera Luisa, Ottolenghi Chris, Garcia-Ortiz J. Elias, Pellegrini Massimo, Manini Francesca, Ko Minoru S H, Nagaraja Ramaiah, Forabosco Antonino, Schlessinger David

Developmental Biology 279 （ 2 ） 271 - 290 2005年03月

ISSN 0012-1606

To identify genes involved in morphogenetic events during mouse ovary development, we started with microarray analyses of whole organ RNA. Transcripts for 60% of the 15,000 gene NIA panel were detected, and about 2000 were differentially expressed in nascent newborn compared to adult ovary. Highly differentially expressed transcripts included noncoding RNAs and newly detected genes involved in transcription regulation and signal transduction. The phased pattern of newborn mouse ovary differentiation allowed us to (1) extend information on activity and stage specificity of cell type-specific genes; and (2) generate a list of candidate genes involved in primordial follicle formation, including podocalyxin (Podxl), PDGFR-β, and a follistatin-domain-encoding gene Flst1. Oocyte-specific transcripts included many (e.g., Deltex2, Bicd2, and Zfp37) enriched in growing oocytes, as well as a novel family of untranslated RNA's (RLTR10) that is selectively expressed in early stage follicles. The results indicate that global expression profiling of whole organ RNA provides sensitive first-line information about ovarian histogenesis for which no in vitro cell models are currently available.

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Discussion (day 2 session 2)

McMahan Jeff, Cohen Jacques, Ko Minoru, Johnson Martin, Robertson John, Murphy Timothy, Brinsden Peter, Hussein Fatima, Savulescu Julian, McLaren Anne, McLean Sheila, Harris John, Schulman Joe, Edwards Robert, Pedersen Roger, Stock Gregory, Grudzinskas Gedis, Boivin Jacky

Reproductive BioMedicine Online 10 （ SUPPL. 1 ） 107 - 110 2005年03月

ISSN 1472-6483

Epigenetics, I GF2 dosage and cancer risk

Kaneda [No Value], Feinberg [No Value], Iacobuzio-Donahue [No Value], Sakatani Takashi, Witzel Sten De Boom, Carter Mark, Ko Minoru, Longo Dan, Okano Hideyuki, Ohlsson [No Value]

Cancer Biology and Therapy 4 （ 3 ） 2005年03月

ISSN 1538-4047

Molecular biology of preimplantation embryos

Ko Minoru S H

Reproductive BioMedicine Online 10 （ SUPPL. 1 ） 80 - 87 2005年03月

ISSN 1472-6483

This article is based on a presentation at the First International Conference on Ethics, Science and Moral Philosophy of Assisted Human Reproduction. The goal is to provide scientific background for the discussion of philosophic issues. Recent advances in the systematic molecular analysis of preimplantation embryos are summarized, including the molecular identification of nearly all genes involved in preimplantation development and their detailed expression patterns. Notwithstanding a quantum leap in molecular understanding of preimplantation embryos, molecular evidence seems to provide no decisive definition of a threshold for the beginning of human life during preimplantation development. © 2005 Reproductive Healthcare Limited.

Transcript copy number estimation using a mouse whole-genome oligonucleotide microarray.

Carter Mark G., Sharov Alexei A., VanBuren Vincent, Dudekula Dawood B., Carmack Condie E., Nelson Charlie, Ko Minoru S H

Genome biology 6 （ 7 ） 2005年

The ability to quantitatively measure the expression of all genes in a given tissue or cell with a single assay is an exciting promise of gene-expression profiling technology. An in situ-synthesized 60-mer oligonucleotide microarray designed to detect transcripts from all mouse genes was validated, as well as a set of exogenous RNA controls derived from the yeast genome (made freely available without restriction), which allow quantitative estimation of absolute endogenous transcript abundance.

Regulation of genome activity and genetic networks in mammals

VanBuren V., Ko M. S H

201 - 220 2004年12月

Age-associated alteration of gene expression patterns in mouse oocytes

Hamatani Toshio, Falco Geppino, Carter Mark G., Akutsu Hidenori, Stagg Carole A., Sharov Alexei A., Dudekula Dawood B., VanBuren Vincent, Ko Minoru S H

Human Molecular Genetics 13 （ 19 ） 2263 - 2278 2004年10月

ISSN 0964-6906

Decreasing oocyte competence with maternal aging is a major factor in human infertility. To investigate the age-dependent molecular changes in a mouse model, we compared the expression profiles of metaphase II oocytes collected from 5- to 6-week-old mice with those collected from 42- to 45-week-old mice using the NIA 22K 60-mer oligo microarray. Among approximately 11 000 genes whose transcripts were detected in oocytes, about 5% (530) showed statistically significant expression changes, excluding the possibility of global decline in transcript abundance. Consistent with the generally accepted view of aging, the differentially expressed genes included ones involved in mitochondrial function and oxidative stress. However, the expression of other genes involved in chromatin structure, DNA methylation, genome stability and RNA helicases was also altered, suggesting the existence of additional mechanisms for aging. Among the transcripts decreased with aging, we identified and characterized a group of new oocyte-specific genes, members of the human NACHT, leucine-rich repeat and PYD-containing (NALP) gene family. These results have implications for aging research as well as for clinical ooplasmic donation to rejuvenate aging oocytes. © Oxford University Press 2004; all rights reserved.

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The status, quality, and expansion of the NIH full-length cDNA project

Gerhard Daniela S., Wagner Lukas, Feingold Elise A., Shenmen Carolyn M., Grouse Lynette H., Schuler Greg, Klein Steven L., Old Susan, Rasooly Rebekah, Good Peter, Guyer Mark, Peck Allison M., Derge Jeffery G., Lipman David, Collins Francis S., Jang Wonhee, Sherry Steven, Feolo Mike, Misquitta Leonie, Lee Eduardo, Rotmistrovsky Kirill, Greenhut Susan F., Schaefer Carl F., Buetow Kenneth H., Bonner Tom I., Haussler David, Kent Jim, Diekhans Mark, Furey Terry, Brent Michael, Prange Christa, Schreiber Kirsten, Shapiro Nicole, Bhat Narayan K., Hopkins Ralph F., Hsie Florence, Driscoll Tom, Soares M. Bento, Bonaldo Maria F., Casavant Tom L., Scheetz Todd E., Brownstein Michael J., Usdin Ted B., Toshiyuki Shiraki, Carninci Piero, Piao Yulan, Dudekula Dawood B., Ko Minoru S H, Kawakami Koichi, Suzuki Yutaka, Sugano Sumio, Gruber C. E., Smith M. R., Simmons Blake, Moore Troy, Waterman Richard, Johnson Stephen L., Ruan Yijun, Lin Wei Chia, Mathavan S., Gunaratne Preethi H., Wu Jiaqian, Garcia Angela M., Hulyk Stephen W., Fuh Edwin, Yuan Ye, Sneed Anna, Kowis Carla, Hodgson Anne, Muzny Donna M., McPherson John, Gibbs Richard A., Fahey Jessica, Helton Erin, Ketteman Mark, Madan Anuradha, Rodrigues Stephanie, Sanchez Amy, Whiting Michelle, Madan Anup, Young Alice C., Wetherby Keith D., Granite Steven J., Kwong Peggy N., Brinkley Charles P., Pearson Russell L., Bouffard Gerard G., Blakesly Robert W., Green Eric D., Dickson Mark C., Rodriguez Alex C., Grimwood Jane, Schmutz Jeremy, Myers Richard M., Butterfield Yaron S N, Griffith Malachi, Griffith Obi L., Krzywinski Martin I., Liao Nancy, Morrin Ryan, Palmquist Diana, Petrescu Anca S., Skalska Ursula, Smailus Duane E., Stott Jeff M., Schnerch Angelique, Schein Jacqueline E., Jones Steven J M, Holt Robert A., Baross Agnes, Marra Marco A., Clifton Sandra, Makowski Kathryn A., Bosak Stephanie, Malek Joel

Genome Research 14 （ 10 B ） 2121 - 2127 2004年10月

ISSN 1088-9051

The National Institutes of Health's Mammalian Gene Collection (MGC) project was designed to generate and sequence a publicly accessible cDNA resource containing a complete open reading frame (ORF) for every human and mouse gene. The project initially used a random strategy to select clones from a large number of cDNA libraries from diverse tissues. Candidate clones were chosen based on 5′-EST sequences, and then fully sequenced to high accuracy and analyzed by algorithms developed for this project. Currently, more than 11,000 human and 10,000 mouse genes are represented in MGC by at least one clone with a full ORF. The random selection approach is now reaching a saturation point, and a transition to protocols targeted at the missing transcripts is now required to complete the mouse and human collections. Comparison of the sequence of the MGC clones to reference genome sequences reveals that most cDNA clones are of very high sequence quality, although it is likely that some cDNAs may carry missense variants as a consequence of experimental artifact, such as PCR, cloning, or reverse transcriptase errors. Recently, a rat cDNA component was added to the project, and ongoing frog (Xenopus) and zebrafish (Danio) cDNA projects were expanded to take advantage of the high-throughput MGC pipeline. © 2004 by Cold Spring Harbor Laboratory Press.

Global gene expression analysis identifies molecular pathways distinguishing blastocyst dormancy and activation

Hamatani Toshio, Daikoku Takiko, Wang Haibin, Matsumoto Hiromichi, Carter Mark G., Ko Minoru S H, Dey Sudhansu K.

Proceedings of the National Academy of Sciences of the United States of America 101 （ 28 ） 10326 - 10331 2004年07月

ISSN 0027-8424

Delayed implantation (embryonic diapause) occurs when the embryo at the blastocyst stage achieves a state of suspended animation. During this period, blastocyst growth is very slow, with minimal or no cell division. Nearly 100 mammals in seven different orders undergo delayed implantation, but the underlying molecular mechanisms that direct this process remain largely unknown. In mice, ovariectomy before preimplantation ovarian estrogen secretion on day 4 of pregnancy initiates blastocyst dormancy, which normally lasts for 1-2 weeks by continued progesterone treatment, although blastocyst survival decreases with time. An estrogen injection rapidly activates blastocysts and initiates their implantation in the progesterone-primed uterus. Using this model, here we show that among ≈20,000 genes examined, only 229 are differentially expressed between dormant and activated blastocysts. The major functional categories of altered genes include the cell cycle, cell signaling, and energy metabolic pathways, particularly highlighting the importance of heparin-binding epidermal growth factor-like signaling in blastocyst-uterine crosstalk in implantation. The results provide evidence that the two different physiological states of the blastocyst, dormancy and activation, are molecularly distinguishable in a global perspective and underscore the importance of specific molecular pathways in these processes. This study has identified candidate genes that provide a scope for in-depth analysis of their functions and an opportunity for examining their relevance to blastocyst dormancy and activation in numerous other species for which microarray analysis is not available or possible due to very limited availability of blastocysts.

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