Department of Physiology and Biophysics, UMDNJ-RWJMS

RESEARCH:

Studying the transcriptional properties of nuclear receptor co-repressors and investigating their involvement in Drosophila development and human diseases.

Rutgers/UMDNJ GRADUATE PROGRAM AFFILLIATION:

Biochemistry

Neuroscience

Cell and Developmental Biology

Physiology and Integrative Biology

Deciphering the mechanisms underlying the transcriptional repressive effects caused by various transcriptional factors at the chromatin level is the research focus of my laboratory. Many human diseases, including cancers and neurological disorders, are caused by aberrant transcriptional repression. My lab is currently studying the transcriptional properties of three different classes of transcriptional co-repressors (see below) and investigating their involvement in nuclear receptor and EGFR (epidermal growth factor receptor) signaling pathways.

These three classes of transcriptional co-repressors are:

1. Atrophin family proteins: they 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-pallidoluysian atrophy (DRPLA), which is a progressive neurodegenerative disease. Mutations of Rere and Atro cause lethality in mouse, zebrafish, and fly during early embryogenesis. Aberrant RERE expression is also implicated in cancer development.

We reported recently that Atrophin proteins are nuclear receptor corepressors (Genes & Development, 2006) and that RERE and Atro, through their associations with histone deacetylase 1/2 and histone H3-K9 methyltransferase G9a, participate in histone H3 (lysine 9) modifications, antagonize EGFR signaling pathways, and specify cell fates (EMBO R., 2008; Nuclear Receptor Signaling, 2008).

2. SMRT family proteins: these include vertebrate silencing mediator of retinoic acid and thyroid hormone receptors (SMRT), vertebrate nuclear receptor co-repressor (N-CoR), and their Drosophila homolog, SMRTER. We isolated SMRTER as a transcriptional corepressor of ecdysone receptor (Molecular Cell, 1999).

We are currently studying the transcriptional properties of SMRTER and investigating its involvement in Drosophila development.

3. Ataxin-1 family proteins: these include vertebrate Ataxin-1 (ATXN1), vertebrate Brother of Ataxin-1 (BOAT), and a Drosophila ATXN1/BOAT-like protein. Glutamine-repeat expansion in ATXN1 causes spinocerebellar ataxia type 1 (SCA1), which is another inherited neurodegenerative disease.

We first identified ATXN1 as a transcriptional coregulator through our discovery that it binds SMRT family proteins and form complexes with HDAC3 both in human cells and in Drosophila ( PNAS, 2004 ). Building on this initial finding, we later identified BOAT, which is a factor related to ATXN1, as a binding factor of both SMRT and ATXN1 ( EMBO J. 2005 ). Through characterizing the properties of BOAT, we further discovered that its expression level is significantly reduced in the Purkinje cells of transgenic SCA1 mouse even before the appearance of ATXN1 nuclear inclusions. This result establishes that altering the properties of BOAT is an early event during the course of pathogenesis of SCA1.

Here are three specific questions that our work would like to address:

(1) How these transcriptional co-repressors recruit histone modifying factors and thus 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, such as EGFR and Notch, to determine cell fates during animal/ Drosophila development.

(3) How aberrant transcriptional repression mediated by these transcriptional co-repressors leads to neurodegenerative diseases or cancers.

Because these transcriptional co-repressors and the signaling pathways they take part in are conserved in different species throughout evolution, my lab uses a combination of cultured human cells and Drosophila to study their properties.

PUBLICATIONS:

Wang, L. and Tsai, C.-C. Atrophin proteins: An overview of a new class of nuclear receptor co-repressors. Nuclear Receptor Signaling, 6, e009 (2008). Review article.

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. 9, 6, 555-62 (2008). Cover Article.

Escher, P, Gouras P, Roduit, R, Tiab, L, Bolay, S, Delarive, T, Chen, S, Tsai, C-C, Hayashi M, Zernant, J, Merriam, JE, Mermod, N, Allikmets, R, Munier, FL, Schorderet, DF. Mutations in NR2E3 can cause dominant or recessive retinal degenerations in the same family. Human Mutation, AOP, Nov. 12 (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). Featured on cover.

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

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). Faculty of 1000 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). Cover Article.