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Department of Dermatology

Department of Dermatology

Yoshihiro Izumiya D.V.M. Ph.D

Yoshihiro Izumiya Yoshihiro Izumiya D.V.M. Ph.D. and his laboratory study epigenetic gene regulation by using herpesvirus reactivation as a model system. Many viruses produce an acute infection in the human host and are then cleared by the immune system. However, other viruses, especially herpesvirus, remain in the infected person till death by producing a chronic latent infection. In latent infection, the herpesvirus hides from the immune system by silencing own gene expression and no infectious virus can be detected during latency. The virus can be reactivated with different external stimuli and will then activate hundreds of gene expression in cascade fashion; this provides us a compelling model to study movement and regulation from “silenced chromatin” to “active chromatin” of host genome.

Our lab is particularly interested in the epigenetic components of chromatin, including host and viral factors that interact to facilitate both the establishment and maintainance of the chromatin state as well as the molecular transitions that take place during reactivation (“chromatin remodeling”). In addition, post-translational modifications that are imparted on critical viral and host factors are also an area of research in our lab. Using a combination of genetic and biochemical approaches, we try to understand the role of host and viral protein modifications such as phosphorylation, methylation, sumoylation and ubiquitinylation on protein function and role in the viral life cycle. Our research provides insights into both the post-translational modifications and chromatin remodeling that takes govern viral latency and reactivation. Moreover, our research may shed new information applicable to other areas of biology, such as cancer, development and aging, where epigenetic regulation has been implicated.

 

Selected Peer Reviewed Publications (out of 44)

1. Datsun A. Hsia, Clifford G. Tepper, Mamata R. Pochampalli, Elaine Y.C. Hsia, Chie Izumiya, Steve B. Huerta, Michael E. Wright, Hong-Wu Chen, Hsing-Jien Kung, and Yoshihiro Izumiya (2010) KDM8, a H3K36me2 histone demethylase that acts in the cyclin A1 coding region to regulate cancer cell proliferation. Proceedings National Academy of Science 107: 9671-9676

2. Pei-Ching Chang, Yoshihiro Izumiya, Chun-Yi Wu, Latricia D. Fitzgerald, Mel Campbell, Thomas J. Ellison, Kit S. Lam, Paul A. Luciw, and Hsing-Jien Kung (2010) Kaposi's sarcoma associated herpesvirus (KSHV) encodes a SUMO E3 ligase which is SIM-dependent and SUMO-2/3-specific. Journal of Biological Chemistry 285: 5266-5273.

3. Paulette F. Suchodolski#, Yoshihiro Izumiya#, Blanca Lupiani, Dharani K. Ajithdoss, Lucy F. Lee, Hsing-Jien Kung and Sanjay M. Reddy (2010) Both homo and heterodimers of Marek's disease virus encoded Meq protein contribute to transformation of lymphocytes in chickens. Virology 399: 312-321 #share first authorship.

4. Yoshihiro Izumiya*, Chie Izumiya, Datsun Hsia, Thomas J. Ellison, Paul A. Luciw, and Hsing-Jien Kung (2009) NF-kappa({kappa})B Serves as a Cellular Sensor of KSHV Latency and Negatively Regulates K-Rta by Antagonizing the RBP-J{kappa} Coactivator. Journal of Virology 83: 4435-4446 *Corresponding author.

5. Thomas J. Ellison#, Yoshihiro Izumiya#*, Chie Izumiya, Paul A. Luciw, and Hsing-Jien Kung (2009) A Comprehensive Analysis of Recruitment and Transactivation Potential of K-Rta and K-bZIP during Reactivation of Kaposi’s Sarcoma-Associated Herpesvirus. Virology 387: 76-88 *Corresponding author #share first authorship.

6. Paulette F. Suchodolski#, Yoshihiro Izumiya#, Blanca Lupiani, Dharani K. Ajithdoss, Oren Gilad, Lucy F. Lee, Hsing-Jien Kung, and Sanjay M. Reddy (2009) Homodimerization of Marek's Disease Virus-Encoded Meq Protein Is Not Sufficient for Transformation of Lymphocytes in Chickens. Journal of Virology 83: 859-869 #share first authorship.

7. Pei-Ching Chang, Latricia D. Fitzgerald, Albert Van Geelen, Yoshihiro Izumiya, Thomas J. Ellison, Don-Hong Wang, David K. Ann, Paul A. Luciw and Hsing-Jien Kung (2009) Kruppel-Associated Box Domain-Associated Protein-1 as a Latency Regulator for Kaposi's Sarcoma-Associated Herpesvirus and Its Modulation by the Viral Protein Kinase. Cancer Research 69: 5681-5689.

8. Oliver Gautschi, Clifford G. Tepper, Phillip R. Purnell, Yoshihiro Izumiya, Christopher P. Evans, Tim P. Green, Pierre Y. Desprez, Primo N. Lara, David R. Gandara, Philip C. Mack, and Hsing-Jien Kung (2008) Regulation of Id1 Expression by Src: Implications for Targeting of the Bone Morphogenetic Protein Pathway in Cancer. Cancer Research 68: 2250-2258.

9. Yoshihiro Izumiya, Chie Izumiya, Albert M. VanGeelen, Don-Hong Wang, Kit S. Lam, Paul A. Luciw, Hsing-Jien Kung (2007) Kaposi's sarcoma-associated herpesvirus-encoded protein kinase and its interaction with K-bZIP. Journal of Virology 81: 1072-1082.

10. Alon M. Levy, Oren Gilad, Liang Xia, Yoshihiro Izumiya, Jonathan Choi, Tsalenko A, Yakhini Z, Richard L. Witter, Lucy F. Lee, Carol J. Cardona, Hsing-Jien Kung. (2005) Meq transforms chicken cells via the v-Jun transcriptional cascade: a converging transforming pathway for Avian oncoviruses. Proceedings National Academy of Science 102:14831-14836 .

11. Yoshihiro Izumiya, Thomas J. Ellison, Edward T.H. Yeh, Jae U. Jung, Paul A. Luciw, Hsing-Jien Kung. (2005) Kaposi’s sarcoma-associated Herpesvirus K-bZIP represses gene transcription via SUMO modification. Journal of Virology 79:9912-9925.

12. M. Sabry Hamza, Richard A. Reyes, Yoshihiro Izumiya, Ron Wisdom R, Hsing-Jien Kung, Paul A. Luciw (2004) ORF36 protein kinase of Kaposi’s sarcoma herpesvirus (KSHV) activates the c-Jun N-terminal kinase (JNK) signaling pathway. Journal of Biological Chemistry 279: 38325-38330.

13. Yorihiro Nishimura, Masayuki Shimojiima, Eiji Sato, Yoshihiro Izumiya, Yukinobu Tohya, Takeshi Mikami, Takayuki Miyazawa. (2004) Downmodulation of CD3epsilon expression in CD8alpha-beta-T cells of feline immunodeficiency virus-infected cats. Journal of General Virology 85: 2585-2589.

14. Yoshihiro Izumiya, Su-Fang Lin, Thomas Ellison, Alon M. Levy, Greg Mayeur, Chie Izumiya, Hsing-Jien Kung. (2003) Cell cycle regulation by KSHV K-bZIP: Direct interaction with cyclin-CDK2 and induction of G1 growth arrest. Journal of Virology 77:9652-61.

15. Alon M. Levy#, Yoshihiro Izumiya#, Peter Brunovskis, Liang Xia, Mark S. Parcells, Sanjay M. Reddy, Lucy Lee, Hong-Wu Chen, Hsing-Jien Kung. (2003) Characterization of the chromosomal binding sites and dimerization partners of the viral oncoprotein Meq in Marek’s Disease Virus transformation T-cells. Journal of Virology 77:12841-12851 #share first authorship.

16. Yoshihiro Izumiya, Su-Fang Lin, Thomas Ellison, Ling-Yu Chen, Chie Izumiya, Paul Luciw, Hsing-Jien Kung (2003) Kaposi’s sarcoma-associated herpesvirus K-bZIP is a co-regulator of K-Rta: Physical association and promoter-dependent transcriptional repression. Journal of Virology 77 (2), 1441-1451.

17. Kentaro Kato, Yoshihiro Izumiya, Yukinobu Tohya, Eiji Takahashi, Kanji Hirai, Yasushi Kawaguchi. (2002) Identification and characterization of Marek’s disease virus serotype 1 (MDV1) ICP22 gene product: MDV1 ICP4 transactivates the MDV1 ICP27 promoter synergistically with MDV1 ICP4. Veterinary Microbiology 85:305-313.

18. Masayuki Shimojima, Yorihiro Nishimura, Takayuki Miyazawa, Kentaro Kato, Kazuya Nakamura, Yoshihiro Izumiya, Hiroomi Akashi, Yukinobu Tohya. (2002) A feline CD2 homologue interacts with human red blood cells. Immunology 105:360-366.

19. Yoshihiro Izumiya, Hyung-Kwan Jang, Mitsuru Ono, Takeshi Mikami (2001) A complete genomic DNA sequence of Marek’s disease virus type 2 strain HPRS24 Current Topics in Microbiology and Immunology 255, 191-221.

20. Hang T. T. Phung, Yasuhiro Ikeda, Takayuki Miyazawa, Kazuya Nakamura, Masami Mochizuki, Yoshihiro Izumiya, Eiji Sato, Yorihiro Nishimura, Yukinobu Tohya, Eiji Takahashi, Takeshi Mikami (2001) Genetic analyses of feline foamy virus isolatesfrom domestic and wild feline species in geographically distant areas. Virus Research 76, 171-181.

21. Yoshihiro Izumiya, Hyung-Kwan Jang, Mitsuru Ono, Takeshi Mikami (2001) The complete DNA sequence of Marek’s disease virus serotype 2. Current Progress on Marek’s Disease Research, 85-90.

22. Yorihiro Nishimura, Masayuki Shimojima, Takayuki Miyazawa, Eiji Sato, Kazuya Nakamura, Yoshihiro Izumiya, Yasuhiro Ikeda, Takeshi Mikami, Eiji Takahashi (2000) Molecular cloning of the cDNAs encoding the feline B-lymphocyte activation antigen B7-1 (CD80) and B7-2 (CD86) homologues which interact with human CTLA-4Ig. European Journal of Immunogenetics 5-6, 427-430.

23. Yoshihiro Izumiya, Hyuug-Kwan Jang, Mie Sugawara, Yasuhiro Ikeda, Ryuichi Miura, Yorihiro Nishimura, Kazuya Nakamura, Takayuki Miyazawa, Chieko Kai, Takeshi Mikami (1999) Identification and transcriptional analysis of the homologues of the herpes simplex virus type 1 UL30 to UL40 genes in the genome of nononcogenic Marek’s disease virus serotype 2. Journal of General Virology 80, 2417-2422.

24. Yoshihiro Izumiya, Hyung-Kwan Jang, Jin-Shun Cai, Yorihiro Nishimura, Kazuya Nakamura, Yoshinori Tsushima, Kentaro Kato, Takayuki Miyazawa, Chieko Kai, Takeshi Mikami (1999) Identification and sequence analysis of the Marek’s disease virus serotype 2 gene homologous to the herpes simplex virus type 1 UL52 protein. Journal of Veterinary Medical Science 61, 683-687.

25. Yorihiro Nishimura, Takayuki Miyazawa, Yasuhiro Ikeda, Yoshihiro Izumiya, Kazuya Nakamura, Jin-Shun Cai, Eiji Sato, Mariko Kohmoto, Takeshi Mikami (1999) Molecular cloning and sequencing of feline CD56 (N-CAM). European Journal of Immunogenetics 26, 29-32.

26. Kazuya Nakamura, Kiyoko Iwatsuki, Yoshihiro Izumiya, Yorihiro Nishimura, Kenjiro Ohashi, Takeshi Mikami, Chieko Kai (1999) Molecular cloning and sequence analysis of the phosphoprotein(P) gene of the lapinized rinderpest virus. Virus Genes 18: 2, 175-178.

27. Yoshihiro Izumiya, Hyung-Kwan Jang, Hiroto Kashiwase, Jin-Shun Cai, Yorihiro Nishimura, Yoshinori Tsushima, Kentaro Kato. Takayuki Miyazawa, Chieko Kai, Takeshi Mikami (1998) Identification and transcriptional analysis of the homologues of the herpes simplex virus type 1 UL41 to UL51 genes in the genome of nononcogenic Marek’s disease virus serotype 2. Journal of General Virology 79, 1997-2001.

 

Yoshihiro Izumiya D.V.M. Ph.D. and his laboratory study epigenetic gene regulation by using herpesvirus reactivation as a model system. Many viruses produce an acute infection in the human host and are then cleared by the immune system. However, other viruses, especially herpesvirus, remain in the infected person till death by producing a chronic latent infection. In latent infection, the herpesvirus hides from the immune system by silencing own gene expression and no infectious virus can be detected during latency. The virus can be reactivated with different external stimuli and will then activate hundreds of gene expression in cascade fashion; this provides us a compelling model to study movement and regulation from “silenced chromatin” to “active chromatin” of host genome.

Our lab is particularly interested in the epigenetic components of chromatin, including host and viral factors that interact to facilitate both the establishment and maintainance of the chromatin state as well as the molecular transitions that take place during reactivation (“chromatin remodeling”). In addition, post-translational modifications that are imparted on critical viral and host factors are also an area of research in our lab. Using a combination of genetic and biochemical approaches, we try to understand the role of host and viral protein modifications such as phosphorylation, methylation, sumoylation and ubiquitinylation on protein function and role in the viral life cycle. Our research provides insights into both the post-translational modifications and chromatin remodeling that takes govern viral latency and reactivation. Moreover, our research may shed new information applicable to other areas of biology, such as cancer, development and aging, where epigenetic regulation has been implicated.

Selected Peer Reviewed Publications (out of 44)

1. Datsun A. Hsia, Clifford G. Tepper, Mamata R. Pochampalli, Elaine Y.C. Hsia, Chie Izumiya, Steve B. Huerta, Michael E. Wright, Hong-Wu Chen, Hsing-Jien Kung, and Yoshihiro Izumiya (2010) KDM8, a H3K36me2 histone demethylase that acts in the cyclin A1 coding region to regulate cancer cell proliferation. Proceedings National Academy of Science 107: 9671-9676

2. Pei-Ching Chang, Yoshihiro Izumiya, Chun-Yi Wu, Latricia D. Fitzgerald, Mel Campbell, Thomas J. Ellison, Kit S. Lam, Paul A. Luciw, and Hsing-Jien Kung (2010) Kaposi's sarcoma associated herpesvirus (KSHV) encodes a SUMO E3 ligase which is SIM-dependent and SUMO-2/3-specific. Journal of Biological Chemistry 285: 5266-5273.

3. Paulette F. Suchodolski#, Yoshihiro Izumiya#, Blanca Lupiani, Dharani K. Ajithdoss, Lucy F. Lee, Hsing-Jien Kung and Sanjay M. Reddy (2010) Both homo and heterodimers of Marek's disease virus encoded Meq protein contribute to transformation of lymphocytes in chickens. Virology 399: 312-321 #share first authorship.

4. Yoshihiro Izumiya*, Chie Izumiya, Datsun Hsia, Thomas J. Ellison, Paul A. Luciw, and Hsing-Jien Kung (2009) NF-kappa({kappa})B Serves as a Cellular Sensor of KSHV Latency and Negatively Regulates K-Rta by Antagonizing the RBP-J{kappa} Coactivator. Journal of Virology 83: 4435-4446 *Corresponding author.

5. Thomas J. Ellison#, Yoshihiro Izumiya#*, Chie Izumiya, Paul A. Luciw, and Hsing-Jien Kung (2009) A Comprehensive Analysis of Recruitment and Transactivation Potential of K-Rta and K-bZIP during Reactivation of Kaposi’s Sarcoma-Associated Herpesvirus. Virology 387: 76-88 *Corresponding author #share first authorship.

6. Paulette F. Suchodolski#, Yoshihiro Izumiya#, Blanca Lupiani, Dharani K. Ajithdoss, Oren Gilad, Lucy F. Lee, Hsing-Jien Kung, and Sanjay M. Reddy (2009) Homodimerization of Marek's Disease Virus-Encoded Meq Protein Is Not Sufficient for Transformation of Lymphocytes in Chickens. Journal of Virology 83: 859-869 #share first authorship.

7. Pei-Ching Chang, Latricia D. Fitzgerald, Albert Van Geelen, Yoshihiro Izumiya, Thomas J. Ellison, Don-Hong Wang, David K. Ann, Paul A. Luciw and Hsing-Jien Kung (2009) Kruppel-Associated Box Domain-Associated Protein-1 as a Latency Regulator for Kaposi's Sarcoma-Associated Herpesvirus and Its Modulation by the Viral Protein Kinase. Cancer Research 69: 5681-5689.

8. Oliver Gautschi, Clifford G. Tepper, Phillip R. Purnell, Yoshihiro Izumiya, Christopher P. Evans, Tim P. Green, Pierre Y. Desprez, Primo N. Lara, David R. Gandara, Philip C. Mack, and Hsing-Jien Kung (2008) Regulation of Id1 Expression by Src: Implications for Targeting of the Bone Morphogenetic Protein Pathway in Cancer. Cancer Research 68: 2250-2258.

9. Yoshihiro Izumiya, Chie Izumiya, Albert M. VanGeelen, Don-Hong Wang, Kit S. Lam, Paul A. Luciw, Hsing-Jien Kung (2007) Kaposi's sarcoma-associated herpesvirus-encoded protein kinase and its interaction with K-bZIP. Journal of Virology 81: 1072-1082.

10. Alon M. Levy, Oren Gilad, Liang Xia, Yoshihiro Izumiya, Jonathan Choi, Tsalenko A, Yakhini Z, Richard L. Witter, Lucy F. Lee, Carol J. Cardona, Hsing-Jien Kung. (2005) Meq transforms chicken cells via the v-Jun transcriptional cascade: a converging transforming pathway for Avian oncoviruses. Proceedings National Academy of Science 102:14831-14836.

11. Yoshihiro Izumiya, Thomas J. Ellison, Edward T.H. Yeh, Jae U. Jung, Paul A. Luciw, Hsing-Jien Kung. (2005) Kaposi’s sarcoma-associated Herpesvirus K-bZIP represses gene transcription via SUMO modification. Journal of Virology 79:9912-9925.

12. M. Sabry Hamza, Richard A. Reyes, Yoshihiro Izumiya, Ron Wisdom R, Hsing-Jien Kung, Paul A. Luciw (2004) ORF36 protein kinase of Kaposi’s sarcoma herpesvirus (KSHV) activates the c-Jun N-terminal kinase (JNK) signaling pathway. Journal of Biological Chemistry 279: 38325-38330.

13. Yorihiro Nishimura, Masayuki Shimojiima, Eiji Sato, Yoshihiro Izumiya, Yukinobu Tohya, Takeshi Mikami, Takayuki Miyazawa. (2004) Downmodulation of CD3epsilon expression in CD8alpha-beta-T cells of feline immunodeficiency virus-infected cats. Journal of General Virology 85: 2585-2589.

14. Yoshihiro Izumiya, Su-Fang Lin, Thomas Ellison, Alon M. Levy, Greg Mayeur, Chie Izumiya, Hsing-Jien Kung. (2003) Cell cycle regulation by KSHV K-bZIP: Direct interaction with cyclin-CDK2 and induction of G1 growth arrest. Journal of Virology 77:9652-61.

15. Alon M. Levy#, Yoshihiro Izumiya#, Peter Brunovskis, Liang Xia, Mark S. Parcells, Sanjay M. Reddy, Lucy Lee, Hong-Wu Chen, Hsing-Jien Kung. (2003) Characterization of the chromosomal binding sites and dimerization partners of the viral oncoprotein Meq in Marek’s Disease Virus transformation T-cells. Journal of Virology 77:12841-12851 #share first authorship.

16. Yoshihiro Izumiya, Su-Fang Lin, Thomas Ellison, Ling-Yu Chen, Chie Izumiya, Paul Luciw, Hsing-Jien Kung (2003) Kaposi’s sarcoma-associated herpesvirus K-bZIP is a co-regulator of K-Rta: Physical association and promoter-dependent transcriptional repression. Journal of Virology 77 (2), 1441-1451.

17. Kentaro Kato, Yoshihiro Izumiya, Yukinobu Tohya, Eiji Takahashi, Kanji Hirai, Yasushi Kawaguchi. (2002) Identification and characterization of Marek’s disease virus serotype 1 (MDV1) ICP22 gene product: MDV1 ICP4 transactivates the MDV1 ICP27 promoter synergistically with MDV1 ICP4. Veterinary Microbiology 85:305-313.

18. Masayuki Shimojima, Yorihiro Nishimura, Takayuki Miyazawa, Kentaro Kato, Kazuya Nakamura, Yoshihiro Izumiya, Hiroomi Akashi, Yukinobu Tohya. (2002) A feline CD2 homologue interacts with human red blood cells. Immunology 105:360-366.

19. Yoshihiro Izumiya, Hyung-Kwan Jang, Mitsuru Ono, Takeshi Mikami (2001) A complete genomic DNA sequence of Marek’s disease virus type 2 strain HPRS24 Current Topics in Microbiology and Immunology 255, 191-221.

20. Hang T. T. Phung, Yasuhiro Ikeda, Takayuki Miyazawa, Kazuya Nakamura, Masami Mochizuki, Yoshihiro Izumiya, Eiji Sato, Yorihiro Nishimura, Yukinobu Tohya, Eiji Takahashi, Takeshi Mikami (2001) Genetic analyses of feline foamy virus isolatesfrom domestic and wild feline species in geographically distant areas. Virus Research 76, 171-181.

21. Yoshihiro Izumiya, Hyung-Kwan Jang, Mitsuru Ono, Takeshi Mikami (2001) The complete DNA sequence of Marek’s disease virus serotype 2. Current Progress on Marek’s Disease Research, 85-90.

22. Yorihiro Nishimura, Masayuki Shimojima, Takayuki Miyazawa, Eiji Sato, Kazuya Nakamura, Yoshihiro Izumiya, Yasuhiro Ikeda, Takeshi Mikami, Eiji Takahashi (2000) Molecular cloning of the cDNAs encoding the feline B-lymphocyte activation antigen B7-1 (CD80) and B7-2 (CD86) homologues which interact with human CTLA-4Ig. European Journal of Immunogenetics 5-6, 427-430.

23. Yoshihiro Izumiya, Hyuug-Kwan Jang, Mie Sugawara, Yasuhiro Ikeda, Ryuichi Miura, Yorihiro Nishimura, Kazuya Nakamura, Takayuki Miyazawa, Chieko Kai, Takeshi Mikami (1999) Identification and transcriptional analysis of the homologues of the herpes simplex virus type 1 UL30 to UL40 genes in the genome of nononcogenic Marek’s disease virus serotype 2. Journal of General Virology 80, 2417-2422.

24. Yoshihiro Izumiya, Hyung-Kwan Jang, Jin-Shun Cai, Yorihiro Nishimura, Kazuya Nakamura, Yoshinori Tsushima, Kentaro Kato, Takayuki Miyazawa, Chieko Kai, Takeshi Mikami (1999) Identification and sequence analysis of the Marek’s disease virus serotype 2 gene homologous to the herpes simplex virus type 1 UL52 protein. Journal of Veterinary Medical Science 61, 683-687.

25. Yorihiro Nishimura, Takayuki Miyazawa, Yasuhiro Ikeda, Yoshihiro Izumiya, Kazuya Nakamura, Jin-Shun Cai, Eiji Sato, Mariko Kohmoto, Takeshi Mikami (1999) Molecular cloning and sequencing of feline CD56 (N-CAM). European Journal of Immunogenetics 26, 29-32.

26. Kazuya Nakamura, Kiyoko Iwatsuki, Yoshihiro Izumiya, Yorihiro Nishimura, Kenjiro Ohashi, Takeshi Mikami, Chieko Kai (1999) Molecular cloning and sequence analysis of the phosphoprotein(P) gene of the lapinized rinderpest virus. Virus Genes 18: 2, 175-178.

27. Yoshihiro Izumiya, Hyung-Kwan Jang, Hiroto Kashiwase, Jin-Shun Cai, Yorihiro Nishimura, Yoshinori Tsushima, Kentaro Kato. Takayuki Miyazawa, Chieko Kai, Takeshi Mikami (1998) Identification and transcriptional analysis of the homologues of the herpes simplex virus type 1 UL41 to UL51 genes in the genome of nononcogenic Marek’s disease virus serotype 2. Journal of General Virology 79, 1997-2001.