Otx2 ChIP-seq reveals unique and redundant functions in the mature mouse retina

PLoS One. 2014 Feb 18;9(2):e89110. doi: 10.1371/journal.pone.0089110. eCollection 2014.


During mouse retinal development and into adulthood, the transcription factor Otx2 is expressed in pigment epithelium, photoreceptors and bipolar cells. In the mature retina, Otx2 ablation causes photoreceptor degeneration through a non-cell-autonomous mechanism involving Otx2 function in the supporting RPE. Surprisingly, photoreceptor survival does not require Otx2 expression in the neural retina, where the related Crx homeobox gene, a major regulator of photoreceptor development, is also expressed. To get a deeper view of mouse Otx2 activities in the neural retina, we performed chromatin-immunoprecipitation followed by massively parallel sequencing (ChIP-seq) on Otx2. Using two independent ChIP-seq assays, we identified consistent sets of Otx2-bound cis-regulatory elements. Comparison with our previous RPE-specific Otx2 ChIP-seq data shows that Otx2 occupies different functional domains of the genome in RPE cells and in neural retina cells and regulates mostly different sets of genes. To assess the potential redundancy of Otx2 and Crx, we compared our data with Crx ChIP-seq data. While Crx genome occupancy markedly differs from Otx2 genome occupancy in the RPE, it largely overlaps that of Otx2 in the neural retina. Thus, in accordance with its essential role in the RPE and its non-essential role in the neural retina, Otx2 regulates different gene sets in the RPE and the neural retina, and shares an important part of its repertoire with Crx in the neural retina. Overall, this study provides a better understanding of gene-regulatory networks controlling photoreceptor homeostasis and disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Chromatin Immunoprecipitation
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology*
  • Gene Ontology
  • Gene Regulatory Networks / genetics*
  • High-Throughput Nucleotide Sequencing / methods
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Mice
  • Microarray Analysis
  • Molecular Sequence Data
  • Otx Transcription Factors / genetics*
  • Otx Transcription Factors / metabolism
  • Otx Transcription Factors / physiology*
  • Regulatory Elements, Transcriptional / genetics
  • Retina / metabolism
  • Retina / physiology*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism


  • Homeodomain Proteins
  • Otx Transcription Factors
  • Otx2 protein, mouse
  • Trans-Activators
  • cone rod homeobox protein

Grants and funding

This work was supported by grants from the CNRS to UMR 7277, ARC-projet 2011-2013 and Retina France-2012 to TL. AS was supported by a fellowship from French Research Ministry and University of Nice, MH was supported by a fellowship from the French Research Ministry and The Fondation Recherche Médicale, BF was supported by a fellowship from French Research Ministry. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.