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October 17 (Wed)

◆Big Hall

<Invited Talks: > 10:00-11:30
Yasushi Okazaki (Saitama Medical Univ. RCGM) 
  Abstract: Mitochondria are small organelles and serve as the powerhouse of the living cells because they generate vital energy (ATP) in their respiratory chain system consisting of protein complexes I to IV and ATPase. Mitochondrial respiratory chain disorder (MRCD) is an intractable disease that develops in childhood. It is a highly frequent inborn error of metabolism that occurs in one out of every 5,000 births. Prominent symptoms develop in such organs as the brain, heart, and muscles, where a great deal of energy is required. In most cases, effective treatment has not been established yet. It is known that various gene abnormalities cause defects of the protein complexes of the respiratory chain, which results in mitochondrial dysfunction. However, identification of the causative gene and the pathogenic mechanism of MRCD remain largely unsolved.
We have started a project to reveal the pathological mechanism of MRCD at the neural cell level using samples obtained from patients with MRCD (http://www.cell-innovation.org/html/program/theme_010_okazaki.html). In this study, various data and findings such as information obtained using high-speed sequencers, knowledge of genome informatics and cell biology, and clinical observations will be utilized to understand why various symptoms develop in a tissue-specific manner in patients with MRCD, while mitochondria are ubiquitously existent in all cells. This study will lead to a comprehensive understanding of the mitochondrial respiratory chain system. We will present current progress and strategy of this project.
Naomichi Matsumoto (Yokohama City Univ. Grad. Sch.of Med.)
  Title: Exome analysis in genetic diseases
  Abstract: Disease-related genome analysis (DGA) has been developed and sophisticated together with technology advances. The advent and frequent update of next generation sequencers (NGSs) can attain the appropriate accuracy for mutation analysis and push DGA into the new stages. We now use Illumina Genome Analyzer (GA) IIx and Hiseq2000 which can produce as much as 60-Gb and 600-Gb sequences in one run, respectively. To focus on genes, we utilized exon capture methods such as SureSelect (Agilent). The current NGS protocol uses 100-108-bp pair-end reads and usually produces 8-9 Gb sequences (per one sample) could be enough for analysis of the whole exome: 90 % of exome bait regions are covered by 8-10 reads or more. Sequences are aligned using MAQ, BWA, Novoalign and commercial-based NextGENe software all of which are able to extract nucleotide changes and small insertions/deletions. The most critical step is the priority scheme selecting variants. We have been successful in addressing culprit mutations in several diseases. I will present our procedures used in our projects including a successful example of Coffin-Siris syndrome.
Shoji Tsuji (The Univ. of Tokyo Hospital)
  Title: Personal genome analyses to elucidate the molecular basis of neurological diseases
  Abstract: Availability of massively parallel sequencing technologies has revolutionized our research paradigm toward better understanding the molecular basis of neurodegenerative diseases. For sporadic diseases (diseases with complex trait), genome-wide association studies (GWAS) based on the “common disease-common variants hypothesis” have been mainly undertaken to elucidate the disease-relevant alleles. Although GWAS have successfully revealed a number of susceptibility genes, odds ratios associated with risk alleles are generally low and account for only a small proportion of estimated heritability. Recent studies have revealed that the effect sizes of the disease-relevant alleles that are identified based on comprehensive resequencing are substantially larger than those identified by GWAS. These findings strongly argue for the role of the “common disease-multiple rare variants hypothesis” in sporadic neurodegenerative diseases. Given the rapidly improving technologies of next generation sequencing (NGS), we expect that NGS will enable us to identify eventually all the variants in an individual’s personal genome. Since there are more than 3,000,000 variations in individual personal genomes, genome informatics is becoming a challenging field in the personal genome analysis.

<Symposium> 13:30-16:30
Hiroshi Tanaka (Tokyo Medical and Dental Univ.)
  Title: Systems pathology of cancer
  Abstract: Systems pathology of cancer metastasis Epithelial-mesenchymal transition (EMT) is now widely recognized as the basic mechanism for cancer invasion and metastasis. From the systems view of the cellular molecular network, EMT could be considered as global “phase transition” of transcription network from the stable cellular network state of epithelial cell to that of mesenchymal cell. We conducted the experimental observation of temporal change of gene expression profile during EMT of retinal pigment epithelium cell line (ARPE-19) caused by TGF-beta and TNF-alpha. The ARACNe algorithm was used to infer structural change of gene regulatory network of about 4000 genes. The global cooperative change of gene expression pattern was observed to suggest the collective structural change of molecular network is taking place during EMT process.
Drug target in protein-protein interaction network We identify the network three-level hierarchical structure of protein interaction networks (PIN) and inquire the distribution of the possible drug targets in this hierarchical structure so that the statistical likelihood of novel drug targets could be inferred. While the average degree of target nodes for cancer drugs was 7.82, the targets for non-cancerous diseases scored only 4.24 (P = 0.01). The reason is considered that, cancer is contracted mostly after reproduction period so that evolutional process has not eliminated cancer disease genes.
Hiroyuki Aburatani (The Univ. of Tokyo)
  Title: Integrated genomic analysis of hepatocellular carcinoma
Satoshi Inoue (The Univ. of Tokyo/ Saitama Medical Univ. RCGM)
  Title: New Androgen Targets in Prostate Cancer
  Abstract: Androgen is a critical factor in prostate cancer. Androgen receptor (AR), a member of nuclear receptor superfamily, mediates androgen action as a transcriptional factor. To explore the AR-mediated gene network in prostate cancer, we performed chromatin immunoprecipitation (ChIP) on array (ChIP-chip) and ChIP-cloning analyses. We identified AR binding sites (ARBSs) and histone H3 acetylated (AcH3) sites as well as AR-target genes such as UGT1A1, CDH2 and APP. We also combined these data with 5’-cap analysis of gene expression (CAGE) and RNA-seq transcriptome analyses. CAGE detected androgen-regulated transcription start sites (TSSs). Both androgen-regulated coding genes and noncoding RNAs (ncRNAs) including microRNAs (miRNAs) were determined as androgen targets. We identified numerous androgen-dependent TSSs that widely distributed throughout the genome, including those in antisense direction of RefSeq genes. The integrated high-throughput approach in cancer provides us useful information for elucidating the AR-mediated transcriptional network that contributes to the development and progression of this disease.
Hiroshi Asahara (Tokyo Medical & Dental Univ.)
  Title: A systems approach reveals that the locomotive systems development and regeneration network
  Abstract: We created a whole-mount in situ hybridization (WISH) database, termed EMBRYS(http://embrys.jp), containing expression data of 1520 transcription factors and cofactors expressed in E9.5, E10.5, and E11.5 mouse embryos--a highly dynamic stage of skeletal myogenesis. This approach implicated 43 genes in regulation of embryonic myogenesis, including a transcriptional repressor, the zinc-finger protein RP58 (also known as Zfp238). Knockout and knockdown approaches confirmed an essential role for RP58 in skeletal myogenesis. Cell-based high-throughput transfection screening revealed that RP58 is a direct MyoD target. Microarray analysis identified two inhibitors of skeletal myogenesis, Id2 and Id3, as targets for RP58-mediated repression. Consistently, MyoD-dependent activation of the myogenic program is impaired in RP58 null fibroblasts and downregulation of Id2 and Id3 rescues MyoD's ability to promote myogenesis in these cells. Our combined, multi-system approach reveals a MyoD-activated regulatory loop relying on RP58-mediated repression of muscle regulatory factor (MRF) inhibitors. We applied our systems approaches to other locomotive tissues research including cartilage and tendon, and revealed novel molecular network regulating joint cartilage development and homeostasis via miRNA-140 (Genes and Development, 2010; Arthritis and Rheum, 2009) and tendon development by Mkx (PNAS, 2010). This approach should benefit reconstruction medicine for cancer therapy.
Masaya Ono (National Cancer Center)
  Abstract: Biomarkers tested by blood sample are greatly expected from the clinician working on daily practice because they will provide useful information to accomplish early and right diagnosis. The comprehensive omics studies are greatly expected for finding such new biomarkers. Our original proteomics analysis system of 2-dimensional image-converted analysis of liquid chromatography and mass spectrometry (2DICAL) has been applied to biomarker discovery from clinical blood samples and succeeded in finding several new blood biomarkers.
In the session, we will introduce the system of 2DICAL, show the biomarkers discovered by 2DICAL, and present the perspective of this technology to cancer therapy.
Edwin Cheung (GIS)
  Title:Genomic and Epigenomic Analyses of Hormone Signaling in Cancer
  Abstract:The transmission of extracellular signals into intracellular responses is a fundamentally important process in biology. Steroid and thyroid hormones are small molecules that function in signal transduction during growth and development. Any aberrations in the signaling pathways controlled by these hormones can lead to disease states. My lab is interested in understanding the underlying mechanisms of nuclear hormone signaling and how they relate to diseases such as cancer. Specifically, we are examining how steroid hormones such as estrogens and androgens regulate the transcriptional activities of the estrogen receptor (ER) and androgen receptor (AR), respectively. Using a combination of molecular and cellular techniques, as well as genomic and bioinformatic approaches, we have mapped the genome wide binding sites (cistrome), chromatin interactions (interactome), and transcripts (transcriptome) mediated by nuclear hormone receptors in cancer cells. Overall, our global and functional analyses revealed that spatial organization is an important and widespread mechanism used in nuclear hormone signaling and collaborative factors are essential molecular determinants in nuclear hormone receptor-mediated chromatin interaction and transcription.  
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