Keiji Tanimoto Dr. Agr. Molecular Genetics

Associate Professor
Many eukaryotic genes (such as globin genes, hox genes, etc.) are organized into gene clusters and the coordinated expression of these genes (in general, their products have similar, but different activities) during development is important for their function. The temporal and spatial control of gene expression from such genes is known to involve long-range chromosomal activation (and/or repression) by regulatory elements, one of such called the locus control region (LCR). However, the way in which an LCR selectively influences individual genes within the locus is not well known. In order to elucidate the mechanistic basis for such a selective interaction between LCR and individual genes, I have been studying the human _eta-globin locus as a prototype. For analyzing such a long-range gene regulation, the introduction of a non-conventional vector system capable of carrying a huge DNA insert (at least 100 kb in the case of globin) is essential; YAC (yeast artificial chromosome) or BAC (bacterial artificial chromosome) fulfill such a requirement. It is also important to employ a host system that would allow both temporal and spatial assessment of gene expression and a transgenic animal system is appropriate for such a purpose. Then, I decided to use a YAC-transgenic mouse (TgM) system in my study and obtained several significant findings that I could encounter only by using such a system.

Now, I am in the process of switching to the BAC-TgM system since it has several benefits when compared with the YAC-TgM system, such as it has less chimerism in the library and the information obtained from the mouse genome project may be directly applicable to this system. I am going to apply this relatively new experimental system to the study of the hematopoiesis/blood pressure regulatory system. Hopefully, I will find something interesting in my research by introducing such technology.

Selected Publications. Tanimoto, K. et al.; Context-dependent EKLF responsiveness defines the developmental specificity of the human epsilon-globin gene in erythroid cells of YAC transgenic mice. Genes & Development, 14, 2778-2794 (2000): Tanimoto, K. et al.; In vivo Modulation of Human beta-globin gene switching. Trends. Cardiovasc. Med., 10, 15-19 (2000): Engel, J.D. et al.; Looping, linking, and chromatin activity: new insights into beta-globin locus regulation. Cell, 100, 499-502 (2000): Alami, R. et al.; Beta-globin YAC transgenes exhibit uniform expression levels but position effect variegation in mice. Hum. Mol. Genet., 9, 631-636 (2000): Tanimoto, K. et al.; The polyoma virus enhancer cannot substitute for DNase I core hypersensitive sites 2-4 in the human beta-globin LCR. Nucleic Acids Res., 27, 3130-3137 (1999): Tanimoto, K. et al.; Effects of altered gene order or orientation of the locus control region on human beta-globin gene expression in mice. Nature, 398, 344-348 (1999): Tanimoto, Y. et al.; Male sterility in transgenic mice expressing activin betaA subunit gene in testis. Biochem. Biophys. Res. Commun., 259, 699-705 (1999): Bungert, J. et al.; Hypersensitive site 2 specifies a unique function within the human beta-globin locus control region to stimulate globin gene transcription. Mol. Cell. Biol., 19, 3062-3072 (1999): Liu, Q. et al.; The A gamma-globin 3' element provides no unique function(s) for human beta-globin locus gene regulation. Proc. Natl. Acad. Sci. USA, 95, 9944-9949 (1998): Tanimoto, K. et al.; Human activin betaA gene. Identification of novel 5' exon, functional promoter, and enhancers. J. Biol. Chem., 271, 32760-32769 (1996): Tanimoto, K. et al.; Angiotensinogen-deficient mice with hypotension. J. Biol. Chem., 269, 31334-31337 (1994)