Shiming Chen, Ph.D.

Professor
Ophthalmology and Visual Sciences
Developmental Biology

Molecular Genetics and Genomics Program
Developmental, Regenerative and Stem Cell Biology Program
Neurosciences Program

  • 314-747-4350

  • 314-747-4351

  • 314-747-4211

  • 8096

  • 617/618 McMillan

  • chenshiming@wustl.edu

  • https://ophthalmology.wustl.edu/items/chen-lab/

  • 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

Research Abstract:

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 (TFs) bound to promoter/enhancer regions of their target genes. We work on deciphering the mechanism of action for each TF, particularly focusing on the Cone-Rod Homeobox (CRX) TF that interacts with both cell type-specific TFs and widely expressed chromatin modulators. CRX mutations 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 TF 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.

Selected Publications:

Brightman DS, Grant RL, Ruzycki PA, Suzuki R, Hennig AK, Chen S. (2018).MLL1 is essential for retinal neurogenesis and horizontal inner neuron integrity. Scientific reports, 8:11902. PMCID: PMC6085291.

Ruzycki PA, Zhang X, Chen S. (2018).CRX directs photoreceptor differentiation by accelerating chromatin remodeling at specific target sites. Epigenetics & chromatin, 11:42. PMCID: PMC6069558.

Ruzycki PA, Linne CD, Hennig AK, Chen S. (2017).
Crx-L253X Mutation Produces Dominant Photoreceptor Defects in TVRM65 Mice. Investigative ophthalmology & visual science, 58:4644. PMCID: PMC5597032.

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.

For more publications, go to http://tiny.cc/ChenS

Last Updated: 8/17/2018 1:45:31 PM

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