Strategic Object

Research Supervisor

Masayuki Yamamoto (Dean / Professor, Tohoku University)

Toshikazu Ushijima (Chief of Division, National Cancer Center Research Institute)

Outline

For healthy life and development of novel strategies for disease prevention, diagnosis, and therapy, this research area focuses on discovery of new principles and establishment of fundamental medical technologies based on epigenome analyses accompanied by biological analyses.
Specifically, this research area invites proposals that identify epigenome alterations useful for identification of etiologies or those critically involved in development and progression of cancers or other chronic disorders, such as arteriosclerosis, diabetes, neurological diseases, and autoimmune diseases. The findings should lead to identification of novel mechanisms for induction of epigenome alteration or maintenance of epigenomes or to innovative strategies for disease prevention, diagnosis, and therapy. This area also invites proposals that, by comparing epigenome profiles during stem cell differentiation, reveal mechanisms of cellular differentiation and establish technologies for robust directed differentiation of various cells to specific lineages. Furthermore, this area invites proposals that develop key technologies for more efficient analysis of methylomes and histone modifications, and for control of epigenomes.
In this research area, JST cooperates with the International Human Epigenome Consortium (IHEC) through some proposals.

Research Area Advisors

・Tsutomu CHIBA
　Professor, Kyoto University

・Akiyoshi FUKAMIZU
　Professor, University of Tsukuba
・Takeo KUBOTA
　Professor, University of Yamanashi

・Ken-ichirou MOROHASHI
　Professor, Kyushu University

・Hozumi MOTOHASHI
　Associate Professor, Tohoku University

・Kazumi NISHIJIMA
　Manager, Mochida Pharmaceutical Co., Ltd.

・Shoji TAJIMA
　Professor, Osaka University

・Toshihisa TAKAGI
　Professor, the University of Tokyo

・Masayo TAKAHASHI
　Team Leader, RIKEN

・Minoru YOSHIDA
　Director, RIKEN

Year Started : 2012

Identification of factors to modify and resist epigenomic alteration induction

Research Director:

Atsushi Kaneda(Associate Professor, The University of Tokyo)

Outline:

Epigenome plays a central role in regulation of cellular behaviors. Cells undergo a programmed, physiological epigenomic alteration under stress, and we will find out modifiers of this “normal” epigenomic alteration. Or, cells must resist induction of aberrant epigenomic alteration that may cause cancer, and we will also discover such resistant factors. We will clarify epigenomic mechanism of life regulation through identification of these modifiers and resistant factors, and disease risk by their aberration.

Epigenome analysis of cells in the placenta and endometrium forming the fetal-maternal interface

Research Director:

Hiroyuki Sasaki

Distinguished Professor and Director, Kyushu University

Outline:

This study aims to determine the reference epigenomes of two cell types of the placenta in an early gestational stage and at term and two cell types (one of them in different hormonal phases) of the endometrium. To this end, we will develop and establish necessary technologies. Furthermore, we will determine the epigenomes of cells from placentae of patients with pregnancy induced hypertension, complete hydatidiform moles, and endometriosis specimens and compare them with the reference epigenomes to identify disease-specific changes. We will also study the methylome of sperm from oligospermic patients to improve assisted reproductive technology.

Basic studies aimed for an epigenome-based therapy: proof of concept in brain function

Research Director:

Yoichi Shinkai

Chief Scientist, RIKEN

Outline:

In this research project, we aim to examine in model mouse 1) how histone lysine methylation is crucial for brain functions and 2) whether the cognition and behavior phenotypes induced by the inactivation of regulating enzyme gene(s) of specific histone lysine methylation can be rescued by the modulation of affected epigenetic mark(s) postnatally. Furthermore, we identify mutation of those regulating enzyme genes in human congenital malformation syndromes and mental disorders. Combination of these studies will provide novel clues for epigenome-based therapy and diagnosis

Molecular regulation and analysis of the establishment of epigenome

Research Director:

Toru Nakano(Professor, Osaka University)

Outline:

Development and differentiation of multicellular organisms can be regarded as the dynamic transition process of epigenomic status. In this project, we will study the molecular functions of the proteins and small non-coding RNA in the establishment of epigenetic status of early embryogenesis and development of germ cells. These two important biological events are critically important events in epigenetic research, because dynamic transition of epigenome occurs during the processes. Although mouse system is utilized in our project, fundamental mechanisms of the establishment of epigenome are same in rodents and human. Our major goals are the molecular understanding of the epigenome establishment and the development of novel methods regulating epigenetic status.

Understanding the epigenetic modifications related to cancer development and regression

Research Director:

Tatsutoshi Nakahata(Professor, Kyoto University)

Outline:

Transient abnormal myelopoiesis (TAM) is a transient hematopoietic condition that occurs 10-20% of newborns with Down syndrome. Although TAM patients exhibit pathological findings that are similar to leukemia patients, TAM regresses spontaneously. This study will use TAM as a model for the development and regression of cancer in order to determine; 1) the alteration of epigenetic profiles during cancer regression, 2) the alteration of epigenetic profiles which leads TAM to leukemia, and 3) the underlying mechanism that provides genomic instability during fatal periods in Down syndrome patients.

Year Started : 2011

Elucidating epigenomeloops of cell differentiation using quantitative ChIP-Seq method

Research Director:

Kazuhiko Igarashi (Professor, Tohoku University)

Outline:

Cell differentiation is based on the processes of selective gene expression. Transcription factors and chromatin, which packages the genome DNA, generate mutual regulatory loops (i.e., epigenome loops), directing specific changes in both transcription factor binding and chromatin structures during cell differentiation. The aim of this project is to understand the structure and function of epigenome loops for cell differentiation.We will focus on the differentiation of plasma cells, which produce antibody, as a model system and apply a new quantitative chromatin immunoprecipitation-sequence (Q-ChIP-Seq) method to compare transcription factor binding and modification of chromatin during their differentiation. This project is expected to reveal fundamental mechanisms of the plasma cell differentiation and immune responses.

Epigenome analysis of mental disorders using advanced technologies

Research Director:

Tadafumi Kato(Head, Riken)

Outline:

When DNA is methylated by the effect of environment, gene expression changes. This might be one of mechanisms underlying mental disorders. However, little is known about the possible role of such epigenetic changes in mental disorders. Because the brain is made from many types of cells, analysis of DNA methylation status of neurons is difficult. In this study, we will develop advanced technologies to analyze epigenome in neurons and examine the neural epigenome in the postmortem brains of patients with mental disorders. In addition, the results are compared with the data in animal models, and causal relationship between epigenomic changes and mental disorders will be elucidated.

Reference epigenome analysis in normal epithelial cells of human digestive system and development of analysis technology

Research Director:

Yae Kanai(Deputy Director, National Cancer Center Research Institute)

Outline:

The aim of this study is to reveal the reference epigenome profiles, the whole picture of mechanisms regulating gene expression, e.g. DNA methylation, chromatin modifications, positions of nucleosomes and variants, and abundance of each RNA species, of human normal cells and contribute to the International Human Epigenome Consortium. We are attempting to make international contributions by epigenome analysis in normal epithelial cells of the digestive system, e.g. the stomach, colon and liver, and development of innovative technologies. Reference epigenome database will be accessible worldwide and promote the innovation of diagnosis and therapy of human diseases through the efficient identification of disease-specific epigenome profiles.

Study of the molecular mechanism in the pluripotency maintenance of stem cells and three-dimensional mapping of the epigenome structure.

Research Director:

Masahiro Shirakawa(Professor, Kyoto University)

Outline:

Pluripotent cells, such as ES and iPS cells, have a unique and characteristic epigenome structure, which is dynamically altered during cell differentiation. The alternation of the entire epigenome structure is facilitated by the modulation of spatial arrangement of DNA methylation/demethylation sites in certain genome region. In this project, we reveal the molecular mechanism underlying the maintenance and alteration of the epigenome structure by studying the structure basis of DNA demethylation and mapping the distribution of DNA methylation/demethylation sites in intranuclear space. We also develop a novel in-cell technique for analyzing maturation and ordering of the cytoskeleton as phenotypic markers reflecting dynamic epigenetic status.

Development of genomic technologies to explore human epigenetic regulation

Research Director:

Shirahige Katsuhiko(Professor, University of Tokyo)

Outline:

Our body consists of more than 250 cell types. While each cell has the same DNA sequence, protein modifications and their binding pattern (so called epigenetic information) defines the specificity of each cell type. The aim of this study is to develop the new standard method to analyze whole picture of epigenetic information and use the method to explore whole-genome epigenetic information of various endothelial cell species. Our ultimate goal is to contribute to the International Human Epigenome Consortium through both epigenomics data and technology development. These data and methods are expected to contribute to basic research and drug discovery as well.

Molecular mechanisms underlying direct reprogramming of fibroblasts to hepatocytes and applications thereof

Research Director:

Atsushi Suzuki

Assocsiate Professor, Kyushu University

Outline:

We have identified specific combinations of transcription factors that can directly convert mouse fibroblasts into cells that closely resemble hepatocytes in vitro. Based on this finding, we next aim to elucidate molecular mechanisms underlying conversion of fibroblasts to hepatocytes and induce hepatocytes from human fibroblasts. Knowledge obtained from this study may lead us to not only discover new principles linking the role of transcription factors to epigenome reconstruction but also develop innovative approaches to treatment of liver diseases.

Mechanism of higher-order epigenome regulation and its medical significance

Research Director:

Mitsuyoshi Nakao(Professor, Kumamoto University)

Outline:

In addition to DNA methylation and histone modification, this study focuses on higher-order epigenome mechanism, especially chromatin loop and nuclear domain formation for essential gene control. From this viewpoint, we will present the spatiotemporal models of disease-related gene loci, leading to the generation of new technologies of cell identification for medical diagnosis and therapy.

Epigenetic drug development to prevent pervasive developmental disorders

Research Director:

Hagiwara Masatoshi(Professor, Kyoto University)

Outline:

Pervasive developmental disorders (PDDs) are characterized by varying degrees of impairment in communication skills, social interactions, and restricted, repetitive and stereotyped patterns of behavior. The preventive measures to reduce the incidence or severity of any type of PDD are not known at this time. In this project, we will make mice models and iPS cells of PDDs, and try to develop the biological markers and therapeutics.

New diagnostic and therapeutic tools targeting epigenetic modulation for lifestyle-related disease Research Director:

Toshiro Fujita(Professor, University of Tokyo)

Outline: