Notch, Nuclear receptors, Transcriptional cofactors, Neural development, Neurodegeneration
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.