4.4 Article

A survey of ancient conserved non-coding elements in the PAX6 locus reveals a landscape of interdigitated cis-regulatory archipelagos

期刊

DEVELOPMENTAL BIOLOGY
卷 387, 期 2, 页码 214-228

出版社

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ydbio.2014.01.007

关键词

Ancient conserved gnathostome enhancers; Reporter transgenics; PAX6; Elephant shark; Long-range enhancers; cis-Regulatory landscape; Regulatory archipelagos

资金

  1. NIH [1RO1 EY01 8000-02]
  2. Medical Research Council UK
  3. Biomedical Research Council of A*STAR, Singapore
  4. Medical Research Council [MC_PC_U127527199, MC_U127527199] Funding Source: researchfish
  5. MRC [MC_U127527199, MC_PC_U127527199] Funding Source: UKRI

向作者/读者索取更多资源

Biological differences between cell types and developmental processes are characterised by differences in gene expression profiles. Gene-distal enhancers are key components of the regulatory networks that specify the tissue-specific expression patterns driving embryonic development and cell fate decisions, and variations in their sequences are a major contributor to genetic disease and disease susceptibility. Despite advances in the methods for discovery of putative cis-regulatory sequences, characterisation of their spatio-temporal enhancer activities in a mammalian model system remains a major bottle-neck. We employed a strategy that combines gnathostome sequence conservation with transgenic mouse and zebrafish reporter assays to survey the genomic locus of the developmental control gene PAX6 for the presence of novel cis-regulatory elements. Sequence comparison between human and the cartilaginous elephant shark (Callorhinchus milii) revealed several ancient gnathostome conserved non-coding elements (agCNEs) dispersed widely throughout the PAX6 locus, extending the range of the known PAX6 cis-regulatory landscape to contain the full upstream PAX6-RCN1 intergenic region. Our data indicates that ancient conserved regulatory sequences can be tested effectively in transgenic zebrafish even when not conserved in zebrafish themselves. The strategy also allows efficient dissection of compound regulatory regions previously assessed in transgenic mice. Remarkable overlap in expression patterns driven by sets of agCNEs indicates that PAX6 resides in a landscape of multiple tissue-specific regulatory archipelagos. (C) 2014 Elsevier Inc. All rights reserved.

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