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

Autor: Vydianathan Ravi, Shipra Bhatia, Sydney Brenner, Byrappa Venkatesh, Dirk A. Kleinjan, Philippe Gautier, Emma Murdoch, Jack M. Monahan, Veronica van Heyningen
Rok vydání: 2014
Předmět:
RNA
Untranslated
Elephant shark
PAX6 Transcription Factor
Xenopus
Long-range enhancers
Locus (genetics)
Regulatory Sequences
Nucleic Acid
Cell fate determination
Eye
Cell Line
Animals
Genetically Modified
Reporter transgenics
Mice
Ancient conserved gnathostome enhancers
Animals
Humans
Paired Box Transcription Factors
Genes
Developmental
Eye Proteins
Promoter Regions
Genetic
Enhancer
Molecular Biology
Gene
Zebrafish
Conserved Sequence
Homeodomain Proteins
Genetics
Base Sequence
biology
Gene Expression Regulation
Developmental
cis-Regulatory landscape
Opossums
Sequence Analysis
DNA
Cell Biology
biology.organism_classification
Regulatory archipelagos
PAX6
Repressor Proteins
Enhancer Elements
Genetic
Evolutionary biology
Regulatory sequence
Vertebrates
Sharks
Chickens
Developmental biology
Developmental Biology
Zdroj: Developmental Biology. 387:214-228
ISSN: 0012-1606
Popis: 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.
Databáze: OpenAIRE
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