Nuclear receptor corepressors and their involvement in transcriptional repression, development, and human dieases

Research Insterests:

Deciphering the mechanisms underlying the transcriptional repressive effects caused by various transcriptional factors has become a burgeoning field in the past few years. Many human diseases, including cancers and neurological disorders, are caused by aberrant transcriptional repression. My lab studies the transcriptional properties associated with three different classes of transcriptional co-repressors, and investigates their involvement in nuclear receptor signaling, animal development, and human diseases.

1. Atrophin family proteins : these include vertebrate Atrophin-1 (ATN1), vertebrate arginine glutamic acid dipeptide repeats protein (RERE) (also called Atrophin-2), and Drosophila Atrophin (Atro) (also called Grunge). Glutamine-repeat expansion in ATN1 causes dentatorubral-phallidolluysian atrophy (DRPLA), which is a progressive neurodegenerative disease.

2. Ataxin-1 family proteins: these include vertebrate Ataxin-1 (ATXN1), vertebrate Brother of Ataxin-1 (BOAT1), and a Drosophila ATXN1/BOAT1-like protein. Glutamine-repeat expansion in ATXN1 causes spinocerebellar ataxia type 1, which is also a progressive neurodegenerative disease.

3. SMRT family proteins: these include vertebrate silencing mediator of thyroid hormone and retinoic acid receptors (SMRT), vertebrate nuclear receptor co-repressor (N-CoR), and their Drosophila homolog, SMRTER. We reported recently that SMRT/N-CoR/SMRTER interact with ATXN1 and BOAT1 and modify their transcriptional properties.

Because these transcriptional corepressors are conserved in evolution, my lab uses a combination of mammalian cell cultures, the mouse system, and the Drosophila system in our investigation. Specific questions that we address are: (1) how these transcriptional co-repressors, by recruiting histone modifying factors, affect chromatin structures in the promoter regions targeted by their associating transcriptional factors; (2) how these transcriptional co-repressors integrate the activities of various chromatin modifying factors and respond to different signaling pathways to determine cell fates during animal/ Drosophila development; and (3) how aberrant transcriptional repression mediated by these transcriptional co-repressors leads to cancers or polyglutamine diseases.

PUBLICATIONS:

Wang, L., Charroux, B., Kerridge, S., Tsai, C.-C. Atrophin recruits HDAC1/2 and G9a to modify histone H3-lysine 9 and to determine cell fates. EMBO Reports. May 2, AOP (2008).

Bolger, T.A., Zhao, X., Cohen, T.J., Tsai, C.-C., Yao , T.P. Neurodegenerative disease protein ataxin-1 antagonizes the neuronal survival function of MEF2. J Bio Chem 282, 29186-92 (2007).

Wang, L., Rajan, H., Pitman, J.L., McKeown, M.M., Tsai, C.-C. Histone deacetylase-associating Atrophin proteins are nuclear receptor co-repressors. Genes & Development 20, 525-530 (2006).

Mizutani, A., Wang, L., Rajan, H., Vig, PJS, Alaynick , WA , Thaler, JP, Tsai, C.-C. Boat, an AXH domain protein, suppresses the cytotoxicity of mutant ataxin-1. EMBO Journal 24, 3339-51 (2005).

Tsai, C.-C., Kao, H.-Y., Mizutani, A., Banayo, E., Rajan. H., McKeown M., and Evans, R. M. Ataxin-1, a SCA1 neurodegenerative disorder protein, is functionally linked to the transcriptional co-repressor of retinoid and thyroid hormone receptors. Proc Natl Acad Sci USA 101, 4047-4052 (2004).

Tsai, C.-C. and Fondell, J. Nuclear receptor recruitment of histone-modifying enzymes to target gene promoters. Vitam Horm . 93-122 (2004). Review article.

Donaldson KM, Li W, Ching KA, Batalov S, Tsai C.-C., Joazeiro CA. Ubiquitin-mediated sequestration of normal cellular proteins into polyglutamine aggregates. Proc Natl Acad Sci USA 100, 8892-8897 (2003).

Pitman, J. L., Tsai, C.-C., Edeen, P. T., Finley, K. D., Evans, R. M., McKeown, M. Multiple mechanisms modify the repressive activity of the DSF nuclear receptor. Developmental Biology 245, 315-328 (2002).

Kao, H.-Y., Verdel, A, Tsai, C.-C., Simon, C, Juguilon, H, Khochbin, S. Mechanism for nucleocytoplasmic shuttling of HDAC7. J Bio Chem 277, 187-193 (2002).

Tsai, C.-C.*, Ghbeish, N.*, Schubiger, M., Zhou, J. Y., Evans, R.M., and McKeown, M. The dual role of Ultraspiracle, the Drosophila RXR, in ecdysone response. Proc Natl Acad Sci USA 98, 3967-3872 (2001). ( * Co-first authors ) .

Shi, Y., Downes, M., Xie, W., Kao, H.-Y., Ordentlich, P., Tsai, C.-C., Hon, M., Evans, R. M. SHARP, an inducible cofactor that integrates nuclear receptor repression and activation. Genes & Development 15, 1140-1151 (2001) .

Tsai, C.-C., Kao, H.-Y., Yao , T.-P., McKeown, M., Evans, R. M. SMRTER, a Drosophila nuclear receptor co-regulator, reveals that EcR-mediated repression is critical for development. Molecular Cell 4, 175-186 (1999).

LAB MEMBERS:

Hongxing (Simon) Gui, Postdoctoral Fellow/RTS-IV

Lei Wang, Graduate Student

Xin Tong, Graduate Student

Bin Zhang, Graduate Student

Mary Lee, Student Assistant

Yijin, Wu, Student Assistant

GRADUATE PROGRAMS AFFILLIATION:

Biochemistry

Neuroscience

Cell and Developmental Biology

Physiology and Integrative Biology