Chen Lab

Shiming Chen, PhD, Professor, Ophthalmology and Visual Sciences Professor, Developmental Biology

Our Mission

  • Decipher the genetic and epigenomic mechanisms regulating photoreceptor gene expression, development and maintenance.
  • Understand pathogenesis underlying blinding disease linked to mutations in photoreceptor transcription factors, particularly the Cone-Rod-Homeobox protein CRX.
  • Develop mechanism-based therapy strategies for treating CRX-associated photoreceptor disease.

Our Approach

Rod and cone photoreceptors are light-sensing neurons essential for our vision. Their development and maintenance require appropriate expression of a set of specific genes while silencing others. Over-expression and under-expression of certain genes, such as the visual pigment Rhodopsin, can lead to photoreceptor developmental defects or degeneration.

The major goal of our research is to elucidate the molecular mechanisms controlling the expression of photoreceptor genes and how genetic mutations cause gene mis-regulation and defects impacting photoreceptor cell biology and survival. We and others have identified a network of photoreceptor-specific transcription factors (TF) acting along with CRX and chromatin modulators that are essential for regulating target gene expression by binding to specific genomic sites called cisregulatory elements (CREs), found in gene promoters, enhancers and other sites.

Our current research focuses on 1) deciphering the regulatory grammar of CRX-CRE interactions and the output that determines where, when and how much each photoreceptor gene is expressed; 2) understanding how mutations in either CRX or CREs disrupt the normal regulation and cause photoreceptor diseases. In vivo and ex vivo functional genomics and high-throughput analyses are being used. Examples are listed below:

 

Omics

  • RNAseq transcriptome analyses from bulk cell populations to single cells.
  • ChIPseq targetome analyses for TF binding and histone modifications.
  • ATACseq for chromatin DNA accessibility.
  • 4Cseq interactome combined with DNA & RNA FISH to study enhancer-promoter contacts and genomic organization in the nucleus.

High-throughput

  • CREseq or massively-parallel-reporter-assays (MPRAs) for functional CREs in the genome, particularly those bound by CRX.
  • CRISPR-Cas9/gRNA mediated genome-wide screens for CREs essential for photoreceptor cell fate.

Disease models

  • Generate mouse models for CRX-linked diseases and investigate the pathogenic mechanisms at morphological, electrophysiological and molecular levels.
  • Develop and test new strategies to correct visual defects caused by human CRX mutations. 

Research Background

Meet The Team

Shiming Chen, PhD

Professor, Ophthalmology and Visual Sciences

 

Director of the Molecular Genetics Core

 

Previous Lab Members

Philip A. Ruzycki Ph.D.   2012-2017 – Ph.D. stduent in Molecular Genetic & Genomics 
Project: Epigenetic regulation of photoreceptor gene expression. 
Current position: Instructor, Ophthalmology & Vision Sciences, Washington University

Diana S. Brightman, Ph.D. 2010-2016 – Ph.D. student in Molecular Cell Biology. 
Project: Histone methyltransferases and demethylases in retinal development. 
Current position: Genetic Conselor, Cincinnati Children’s Hospital.

Nicholas M.A. Tran, Ph.D. 2008-2014 – Ph.D. student in Molecular Genetics & Genomics
Project: The mechanisms by which human CRX mutations cause dominant retinopathies.
Current position:
Postdoctoral Associate with Dr. Josh Sanes at Harvard University

Guang-Hua Peng, M.D., Ph.D. 2002-2011 – Senior Staff Scientist.
Current position: Professor, Hernan University School of Med, China

Xin Fang, B.S. 2017-2018 – Research Technician II
Project: The histone methyltransferases MLL1 and MLL2 in retinal development and maintenance.
Current position: Dental student, University of the Pacific Dugoni School of Dentistry

Courtney D. Linne, B.A. 2016-2017 – Research Technician II and Undergraduate Research Assistant.
Project: Animal models of CRX-associated blinding diseases.
Current position:
M.D./Ph.D. student, University of Cincinnati College of Medicine.

Hui Wang, M.D. 2006-2013 –   Research Technician II.
Project: Mouse models of blinding diseases. 

Rachel L. Grant, B.A. 2013-2015 –  Undergraduate Research Assistant
Project: The histone methyltransferase MLL1 in retinal development and maintenance.
Current position: Ph.D. student in Developmental Biology, Stanford University.

Ray Suzuki, B.A. 2011-2013 – Undergraduate Research Assistant 
Project: The histone methyltransferase MLL1 in retinal development and maintenance.
Current position: Technical Consultant, Phenomenex Company.

Chen Lab Photo Album

Publications

View Shiming Chen’s NCBI publications on PubMed»

  1. MLL1 is essential for retinal neurogenesis and horizontal inner neuron integrity. Brightman DS, Grant RL, Ruzycki PA, Suzuki R, Hennig AK, Chen S. Scientific reports. 2018; 8(1):11902.
  2. CRX directs photoreceptor differentiation by accelerating chromatin remodeling at specific target sites. Ruzycki PA, Zhang X, Chen S. Epigenetics & chromatin. 2018; 11(1):42.
  3. Crx-L253X Mutation Produces Dominant Photoreceptor Defects in TVRM65 Mice.  Ruzycki PA, Linne CD, Hennig AK, Chen S. Investigative ophthalmology & visual science. 2017; 58(11):4644
  4. CrxRdy Cat: A Large Animal Model for CRX-Associated Leber Congenital Amaurosis.Occelli LM, Tran NM, Narfström K, Chen S, Petersen-Jones SM. Investigative Ophthalmology & Visual Science. 2016; 57(8):3780-92.
  5. Nrl-Cre transgenic mouse mediates loxP recombination in developing rod photoreceptors. Brightman DS, Razafsky D, Potter C, Hodzic D, Chen S. Genesis 2016; 54(3):129-35.
  6. Graded gene expression changes determine phenotype severity in mouse models of CRX-associated retinopathies. Ruzycki PA, Tran NM, Kefalov VJ, Kolesnikov AV, Chen S. Genome Biology. 2015; 16:171.
  7. The transcription factor GTF2IRD1 regulates the topology and function of photoreceptors by modulating photoreceptor gene expression across the retina. Masuda T, Zhang X, Berlinicke C, Wan J, Yerrabelli A, Conner EA, Kjellstrom S, Bush R, Thorgeirsson SS, Swaroop A, Chen S, Zack DJ. Journal of Neuroscience 2014; 34(46):15356-68.
  8. Mechanisms of blindness: animal models provide insight into distinct CRX-associated retinopathies. Tran NM, Chen S. Developmental Dynamics. 2014; 243(10):1153-66.
  9. Mechanistically distinct mouse models for CRX-associated retinopathy. Tran NM, Zhang A, Zhang X, Huecker JB, Hennig AK, Chen S. PLoS Genetics. 2014; 10(2):e1004111.
  10. Transcription coactivators p300 and CBP are necessary for photoreceptor-specific chromatin organization and gene expression. Hennig AK, Peng GH, Chen S. PLoS One. 2013; 8(7):e69721.
  11. Active opsin loci adopt intrachromosomal loops that depend on the photoreceptor transcription factor network. Peng GH, Chen S. Proceedings of the National Academy of Sciences of the United States of America. 2011; 108(43):17821-6.
  12. Pias3-dependent SUMOylation controls mammalian cone photoreceptor differentiation. Onishi A, Peng GH, Chen S, Blackshaw S. Nature Neuroscience. 2010; 13(9):1059-65