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Division of Gene Structure and Function Division of Gene Regulation and Signal Transduction
Division of Developmental Biology Division of Pathophysiogy
Division of Functional Genomics & Systems Medicine Division of Gene Therapy
Division of Translational Research  
Division of Gene Structure and Function
概要 Research Summary
 

Transcriptional regulation of gene expression in eukaryotic cells is one of the central problems in modern medicine and biology. The Kurokawa laboratory is interested in elucidating the mechanism of the transcriptional regulation. For this purpose we have been utilizing nuclear hormone receptor (NR) as a model system. We are also performing to dissect onset of human genetic diseases induced by disorder of transcriptional regulation and, to develop the effective treatment for the diseases.

Our group has demonstrated that coactivator and corepressor (cofactors) are essential for the transcriptional regulation by NR. It has been shown that coactivator possesses intrinsic histone acetylase (HAT) activity and corepressor is associated with histone deacetylase (HDAC). These enzyme activities turn out to be indispensable for the function of these cofactors (Figure 1). Recently, we have obtained series of results to show that dysregulation of the HAT activity causes human genetic diseases such as Rubinstein-Taybi Syndrome (RTS) and Huntington's disease.

Our present efforts are to identify biochemical and biological roles of HAT activity in eukaryotic transcriptional regulation. Recently we have found an RNA-binding protein, TLS (translocated in liposarcoma) which has potent inhibitory effect on the HAT activity of CREB-binding protein (CBP). Our results show that this inhibitory molecule has a regulatory role in the CREB-dependent transcription systems. Only two genes, cyclin D1 and cyclin E1, out of more than 250 CREB-dependent genes were targeted by TLS to reduce their expression. Non-coding RNAs transcribed from the promoter region of cyclin D1 were bound with TLS and specifically reduced the transcription of cyclin D1 gene itself. The data suggest a novel model of a mechanism of transcription, RNA-dependent transcriptional repression through TLS (Nature in press, 2008, Figure 2). Now, we are trying to generalize the model for other promoter systems.

The DNA sequence information from the human genome project alone turns out to be not enough to elucidate the biological function of human genes. It is likely that hidden information encoded by chromatin structures should confer the differences between human and chimpanzee, also between two individuals. The research for chromatin structures contains a lot of unsolved problems. Solving some of these problems should deserve a Nobel Prize. Now, we are getting a novel horizon of transcriptional regulation with non-coding RNA and developing it further.

 

Figure1

 

Figure2

スタッフ Staff
Professor Riki Kurokawa
Instructor Ryoma Yoneda
Assistant Naomi Ueda
Post doctor Cui Wei
Project Technical Assistant Emika Sekido
Visiting Assistant Professor Akio Matsushita
テーマ Research Projects
We are always aiming at top journals. The followings are present on-going projects.
1.
Characterization of HAT regulatory molecules.
2.
Fundamental understanding of transcriptional regulation through nuclear receptors.
3.
Analysis of non-coding RNA-dependent transcriptional regulation.
links Link to collaborative laboratories
1.
Dr. Christopher K. Glass, University of California, San Diego
2.
Dr. Michael G. Rosenfeld, Howard Hughes Medical Institute University of California, San Diego
文献 Selected Publications
Fujimoto K, Kurokawa R. Development of a mouse monoclonal antibody for the detection of asymmetric dimethylarginine of Translocated in LipoSarcoma/FUsed in Sarcoma and its application in analyzing methylated TLS. Cell & Bioscience 4:77, (2014)
[PMID: 25810899]
Wada T, Araki Y, Sato K, Yokota K, Kim Y, Oda H, Kurokawa R, Mimura T.Aberrant histone acetylation contributes to elevated interleukin-6 production in rheumatoid arthritis synovial fibroblasts. BBRC 444: 682-686 (2014).
[PMID: 24513290]
Kurokawa R. Generation of functional long noncoding RNA through transcription and natural selection. Regulatory RNAs, Chapter 6, Springer Berlin Heidelberg 151-174 (2011)
Kurokawa R. Promoter-associated long noncoding RNAs repress transcription through a RNA binding protein TLS. Adv Exp Med Biol 722:196-208 (2011)
[PMID: 21915790]
Takahama K, Sugimoto C, Arai S, Kurokawa R, Oyoshi T. Loop Lengths of G-Quadruplex Structures Affect the G-Quadruplex DNA Binding Selectivity of the RGG Motif in Ewing's Sarcoma. Biochemistry 50: 5369-5378 (2011)
[PMID: 21561087]
Du K, Arai S, Kawamura T, Matsushita A, Kurokawa R. TLS and PRMT1 synergistically coactivate transcription at the survivin promoter through TLS arginine methylation. BBRC 404: 991-996 (2011)
[PMID: 21187067]
Kurokawa R. Long noncoding RNA as a regulator for transcription. Progress in Molecular and Subcellular Biology 51: 29-41 (2011)
[PMID: 21287132]
Kurokawa R, Rosenfeld M.G, Glass C.K. Transcriptional regulation through noncoding RNAs and epigenetic modifications. Point of View article. RNA Biology 6:233-236 (2009)
[PMID: 19411842]
Wang X, Arai S, Song X, Reichart D, Du K, Pascual G, Tempst P, Rosenfeld M.G, Glass CK, Kurokawa R. Induced ncRNAs allosterically modify RNA binding proteins in cis to inhibit transcription. Nature 454: 126-130 (2008)
[PMID: 18509338]
Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL, Kazantsev A, Schmidt E, Zhu Y-Z, Greenwald M, Kurokawa R, Housman DE, Jackson GR, Marsh JL, Thompson LM. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413: 739-743 (2001)
[PMID: 11607033]
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