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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
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