Shiming Chen, Ph.D.
Ophthalmology and Visual Sciences
Molecular Genetics and Genomics Program
Developmental, Regenerative and Stem Cell Biology Program
Gene expression regulation, transcription factors, epigenetic regulators, photoreceptor development and degeneration, mouse models, gene therapy
Molecular mechanisms regulating photoreceptor gene expression in healthy and diseased retinas
Rod and cone photoreceptors in the retina convert light to neuronal signals. Development and maintenance of these unique neurons require precisely regulated expression of a set of genes that are critical for cell type-specific function. Over-expression or under-expression of certain of these genes can lead to developmental defects or degeneration. Our laboratory studies the molecular mechanisms governing this regulation, explores the implications of these mechanisms in understanding photoreceptor diseases caused by misregulation, and develops treatment strategies. We have recently discovered that regulation of photoreceptor gene expression can occur at both RNA synthesis (transcription) and degradation (RNA stability) levels. Transcriptional regulation is mediated by a network of photoreceptor transcription factors bound to promoter/enhancer regions of their target genes. We have specifically focused on two of these factors, the cone-rod homeobox protein CRX and the orphan nuclear receptor NR2E3, both of which are linked to blinding human diseases. For RNA stability regulation, we are investigating its role and contribution (prevalence and degree) to overall photoreceptor gene expression in normal and diseased retinas and the key regulators, i.e. RNA-binding proteins. Specific projects and laboratory techniques used are follows:
1) Determine the role of gene expression regulators in photoreceptor development and maintenance, using loss-of-function and gain-of-function mouse model studies.
2) Investigate mechanisms of action for key regulators, using protein-protein, protein-DNA and protein-RNA interaction and post-translational modification assays.
3) Decipher the cellular and molecular mechanisms by which mutations in the photoreceptor transcription factor CRX cause blinding diseases by creating and characterizing knock-out/knock-in mouse models. Genotype–phenotype correlations are revealed using morphological, electrophysiological and biochemical assays.
4) Determine the importance of epigenetic regulation in rod vs. cone gene expression and differentiation, particularly focusing on mechanisms involving differential histone modifications and 3D chromosomal organizations in nuclear territories.
5) Develop mechanism-based therapy in mouse models of photoreceptor disease, including recombinant AAV-mediated gene delivery and small-molecule epigenetic modulators.
For each project, state-of-the-art multidisciplinary approaches are being used, including the most up-to-date functional genomics and bioinformatics tools. Collaboration with experts in each discipline is encouraged. These studies will enhance our understanding of retinal photoreceptor development and diseases and provide new avenues for developing treatment strategies with the ultimate goal of translating this research into clinical practice.
Ruzycki PA, Tran NM, Kefalov VJ, Kolesnikov AV, Chen S. (2015). Graded gene expression changes determine phenotype severity in mouse models of CRX-associated retinopathies.
Genome biology, 16:171. PMCID: PMC4556057.
Tran NM, Zhang A, Zhang X, Huecker JB, Hennig AK, Chen S. (2014). Mechanistically distinct mouse models for CRX-associated retinopathy.
PLoS Genet, 10(2):e1004111. PMCID: PMC3916252.
Hennig AK, Peng GH, Chen S. (2013). Transcription Coactivators p300 and CBP Are Necessary for Photoreceptor-Specific Chromatin Organization and Gene Expression.
PLoS One, 8(7):e69721. PMCID: PMC3724885.
Peng, G.-H. & Chen, S. (2011). Active opsin loci adopt intrachromosomal loops that depend on the photoreceptor transcription factor network.
Proc Natl Acad Sci USA 108(43):17821-17826. PMCID:PMC3203788.
Onishi, A., Peng, G.-H., Chen, S., & Blackshaw, S. (2010). Pias3-dependent SUMOylation controls mammalian cone photoreceptor differentiation.
Nature Neuroscience, 13(9):1059-1065. PMCID:PMC2932661
Onishi, A.*, Peng, G.-H.*, Hsu, C., Alexis, U., Chen, S#, & Blackshaw, S#. (2009). Pias3-Dependent SUMOylation Directs Rod Photoreceptor Development.
Neuron, 61(2): 234-246. PMCID:PMC2701228 (Recommended reading by Faculty of 1000) *Equal-contributing first authors. #Co-corresponding authors.
Peng, G.-H. & Chen, S. (2007). Crx activates opsin transcription by recruiting HAT-containing co-activators and promoting histone acetylation.
Hum Mol Genet, 16(20):2433-2452. PMCID:PMC2276662 (Cover article).
For more publications, go to http://tiny.cc/ChenS
Last Updated: 8/22/2016 2:21:16 PM