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Regulation of photoreceptor gene expression in retinal development and disease
Development and maintenance of rod and cone photoreceptor cells in the retina require precisely regulated expression of a set of genes (photoreceptor transcriptome) that are essential for photoreceptor function.  Over-expression and under-expression of certain genes in photoreceptor transcriptome can lead to developmental defects or photoreceptor degeneration.  The major goal of our research is to elucidate the molecular mechanisms controlling the expression of these photoreceptor genes.

Regulation of photoreceptor gene expression is mediated by interactions between photoreceptor transcription factors and promoter/enhancer region of the photoreceptor genes.  We have focused our research on identifying transcription factors that serve as molecular "switches" for expressing photoreceptor genes.  One such switch is the cone-rod homeobox protein Crx, which binds to and activates the transcription of both rod and cone genes.  Crx mutations are associated with various forms of photoreceptor diseases such as cone-rod dystrophy and Leber congenital amaurosis.  Thus, Crx is required for the development and maintenance of rod and cone function.  Another transcription factor that we are working on is the orphan photoreceptor nuclear receptor Nr2e3 (or PNR), which is involved in rod differentiation and maintenance by activating the transcription of rod genes but repressing that of cone genes.  Nr2e3 is also associated with a degeneration disease called enhanced S-cone syndrome (ESCS).  

To further elucidate the role and mechanisms of action for Crx and Nr2e3, molecular biological and biochemical approaches are being used to identify the regulatory network associated with these two proteins.  These approaches include: 1) protein-protein interaction screens to identify their interacting partners and various assays to characterize these partners; 2) transgenic mouse, cell transfection and protein-DNA binding assays to identify DNA elements and protein factors that regulate Crx expression; 3) genome-wide chromatin immunoprecipitation (ChIP) assays to identify in vivo targets of Crx, Nr2e3 and their associated proteins and defects in target binding due to disease-causing mutations; 4) biochemical and animal model studies to investigate the molecular mechanisms by which mutations in Crx, Nr2e3 and their associated factors cause photoreceptor degeneration. Based on these mechanisms, pharmacological approaches are being developed to treat the diseases caused by these mutations.  Our studies will provide important information for understanding the normal and diseased retina and could lead to new therapeutic interventions.


Research Publications

Peng G-H and Chen S: Crx activates opsin transcription by recruiting HAT-containing co-activators and promoting histone acetylation.  Hum. Mol. Genet. 16:2433-2452, 2007. (Cover article) Full Article >

Hennig AK, Peng G-H and Chen S: Regulation of photoreceptor gene expression by Crx-associated transcription factor network.  Brain Res.  2007, in press. 10.1016/j.brainres.2007.06.036 Full 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 U S A,  102:8472-8477, 2005.   Full Article >

Peng GH, Ahmad O, Ahmad F, Liu J, Chen S (2005 Mar 15). The photoreceptor-specific nuclear receptor Nr2e3 interacts with Crx and exerts opposing effects on the transcription of rod versus cone genes. Hum Mol Genet. 14 (6): 747-64. Full Article >

Chen S, Peng G, Wang X, Smith AC, Grote SK, Sopher BL and La Spada AR: Interference of Crx-dependent transcription by ataxin-7 involves interaction between the glutamine regions and requires the ataxin-7 carboxy-terminal region for nuclear localization. Hum Mol Genet, 13:53-67, 2004. Full Article >

La Spada AR, Fu YH, Sopher BL, Libby RT, Wang X, Li LY, Einum DD, Huang J, Possin DE, Smith AC, Martinez RA, Koszdin KL, Treuting PM6, Ware CB, Hurley JB, Ptacek LJ, Chen S. Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7.  Neuron, 31:913-927, 2001.
 Full Article >

Contact Info
Shiming Chen, Ph.D
Office Location: 617 McMillan
Office Phone: 314-747-4350
Lab Phone: 314-747-4351
Campus Box: 8096
Fax: 314-747-4211

chen@vision.wustl.edu
http://ophthalmology.wustl.edu/faculty/chen/index.html