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Characterization of Atrophin Proteins, a Novel Class of Nuclear Receptor Corepressors

by
Lei Wang
Master of Science, 2001
Zhongshan University
People`s Republic of China

Thesis Advisor: Chih-Cheng Tsai, PhD

Graduate Program of Physiology and Integrative Biology

CABM 010

Friday, March 28, 2008
2:30 pm


Abstract

Drosophila Tailless (Tll), which is an orphan nuclear receptor, plays important roles in embryonic segmentation and neurogenesis. Both Tll and its vertebrate homologue Tlx can exert potent transcriptional repression activity. However, the underlying molecular mechanism had remained undetermined. In a yeast two-hybrid screen, Drosophila Atrophin (Atro, also called Grunge) was identified as a specific Tll/Tlx interacting factor, which, together with two related proteins, the vertebrate Atrophin-1 (ATN1) and vertebrate arginine glutamic acid repeats encoded (RERE, also called Atrophin-2), constitutes the Atrophin protein family. This thesis is focused on the characterization of Atrophin proteins as a novel class of nuclear receptor corepressors.

With detailed domain mapping, Atro was found to directly interact with the ligand binding domain (LBD) of Tll/Tlx via its C-terminal region. This interaction is conserved among all three Atrophin proteins. In addition, they also can interact with more nuclear receptors such as the chicken ovalbumin upstream promoter-transcription factor (COUP-TF) and Drosophila Seven-up (SVP). The genetic interaction between Atrophin proteins and Tll/Tlx was investigated by taking advantage of the known role of Tll in Drosophila embryonic segmentation. We demonstrated that Atro is required by Tll to repress the transcription of a gap gene, knirps (kni), and to control cell fate determination. The observation that Atro is present on the kni promoter further confirmed this conclusion. When studying the repression mechanism of Atrophin proteins, we found out that RERE can exert histone deacetylase (HDAC) and histone lysine methyltransferase (HMT) activities by recruiting HDAC1/2 and G9a through its ELM2 (EGL-27 and MTA1 homology 2) and SANT (SWI3/ADA2/N-CoR/TFIII-B) domains. These sequential modes of actions that lead to stable methylation of histone H3-K9 are common features shared by other ELM2-SANT containing proteins. The physiological relevance of these interactions was established by our discovery that Drosophila G9a and Rpd3 (the fly HDAC1) collaborate with Atro to repress vein formation in the wing and tissue melanization in the head. Our study proves that Atrophin proteins are a novel class of nuclear receptor corepressors, which integrate histone deacetylation and methylation to repress gene transcription and to control animal development.


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