Research Abstract:
Rod and cone photoreceptors in the retina convert light to neuronal signals. Development and maintenance of these neurons require precisely regulated expression of a set of genes (the photoreceptor transcriptome) that are critical for photoreceptor function. Over-expression or under-expression of certain of these genes can lead to developmental defects or photoreceptor degeneration. Our laboratory studies the molecular mechanisms that control this expression and the implications of these mechanisms in disease pathogenesis and treatments.
Photoreceptor gene transcription is regulated by interactions between a network of transcription factors and promoter/enhancer elements on the target genes. We have focused on two of the factors, the cone-rod homeobox protein Crx and nuclear receptor Nr2e3, both of which are linked to human photoreceptor diseases, including Leber's congenital amaurosis, cone-rod dystrophy and retinitis pigmentosa. We investigate the function and regulatory network associated with Crx and Nr2e3 using molecular biological and biochemical approaches: 1) protein-protein interaction assays to identify and characterize their interacting partners; 2) transgenic mouse, cell transfection and protein-DNA binding assays to identify DNA elements and protein factors that regulate their expression; 3) chromatin immunoprecipitation (ChIP) assays to identify direct targets of the two proteins and their co-factors, and defects in target binding due to disease-causing mutations; 4) ChIP and chromosome conformation capture (3C) assays to reveal epigenetic changes, including histone modifications and intrachromosomal interactions, of rod and cone genes during retinal development and disease; 5) knock-out/knock-in mouse studies to investigate the mechanisms by which mutations in Crx, Nr2e3 and their associated factors cause photoreceptor degeneration; 6) mechanism-based therapy development using cultured cells and knock-out/knock-in mutant mice as models, including AAV-mediated gene delivery and small epigenetic modulators. These studies together will greatly enhance our understanding of the cellular and molecular basis of photoreceptor degeneration diseases and provide new avenues and animal models for therapy development.
Selected Publications:
Onishi A*, Peng G-H*, Hsu C, Alexis U, Chen S#, Blackshaw S#: Pias3-Dependent SUMOylation Directs Rod Photoreceptor Development. Neuron 2009 61: 234-246. (Recommended reading by Faculty of 1000) *Equal-contributing first authors. #Co-corresponding authors.
Hennig AK, Peng G-H and Chen S. Regulation of photoreceptor gene expression by Crx-associated transcription factor network. Brain Res 2008 1192:114-133.
Peng G-H and Chen S. Crx activates opsin transcription by recruiting HAT-containing co-activators and promoting histone acetylation. Hum Mol Genet 2007 16:2433-2452. (Cover article)
Palhan VB, Chen S, Peng GH, Tjernberg A, Gamper AM, Fan Y, Chait BT, La Spada AR, Roeder RG. Polyglutamine-expanded ataxin-7 inhibits STAGA histone acetyltransferase activity to produce retinal degeneration. Proc Natl Acad Sci USA 2005 102:8472-8477.
Peng G-H, Ahmad O, Ahmad F. Liu J, Chen S. The photoreceptor-specific nuclear receptor Nr2e3 interacts with Crx and exerts opposing effects on the transcription of rod versus cone genes. Hum Mol Genet 2005 14:747-764.
Last Updated: 09/10/2009 |