4.7 Article

Cis-regulatory dissection of cone development reveals a broad role for Otx2 and Oc transcription factors

期刊

DEVELOPMENT
卷 148, 期 9, 页码 -

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COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.198549

关键词

Cis-regulatory module; CRM; Enhancer; Chromatin; Gene regulatory network; GRN; Photoreceptor; Cone; Horizontal cell; Retina; Otx2; Onecut; Chick

资金

  1. Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung [151974, 171521]
  2. Human Frontier Science Program
  3. National Institutes of Health [EYO 29771, HD032443]
  4. Howard Hughes Medical Institute

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The study identified the important role of transcription factors Otx2 and Oc1 in coordinating cone development and function, and discovered many new cis-regulatory modules (CRMs) that could potentially be used as useful reagents for gene therapy of cone diseases.
The vertebrate retina is generated by retinal progenitor cells (RPCs), which produce >100 cell types. Although some RPCs produce many cell types, other RPCs produce restricted types of daughter cells, such as a cone photoreceptor and a horizontal cell (HC). We used genome-wide assays of chromatin structure to compare the profiles of a restricted cone/HC RPC and those of other RPCs in chicks. These data nominated regions of regulatory activity, which were tested in tissue, leading to the identification of many cis-regulatory modules (CRMs) active in cone/HC RPCs and developing cones. Two transcription factors, Otx2 and Oc1, were found to bind to many of these CRMs, including those near genes important for cone development and function, and their binding sites were required for activity. We also found that Otx2 has a predicted autoregulatory CRM. These results suggest that Otx2, Oc1 and possibly other Onecut proteins have a broad role in coordinating cone development and function. The many newly discovered CRMs for cones are potentially useful reagents for gene therapy of cone diseases.

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