title: Systematic human/zebrafish comparative identification of cis-regulatory activity around vertebrate developmental transcription factor genes.
abstract: Pan-vertebrate developmental cis-regulatory elements are discernible as highly conserved noncoding elements (HCNEs) and are often dispersed over large areas around the pleiotropic genes whose expression they control. On the loci of two developmental transcription factor genes, SOX3 and PAX6, we demonstrate that HCNEs conserved between human and zebrafish can be systematically and reliably tested for their regulatory function in multiple stable transgenes in zebrafish, and their genomic reach estimated with confidence using synteny conservation and HCNE density along these loci. HCNEs of both human and zebrafish function as specific developmental enhancers in zebrafish. We show that human HCNEs result in expression patterns in zebrafish equivalent to those in mouse, establishing zebrafish as a suitable model for large-scale testing of human developmental enhancers. Orthologous human and zebrafish enhancers underwent functional evolution within their sequence and often directed related but non-identical expression patterns. Despite an evolutionary distance of 450 million years, one pax6 HCNE drove expression in identical areas when comparing zebrafish vs. human HCNEs. HCNEs from the same area often drive overlapping patterns, suggesting that multiple regulatory inputs are required to achieve robust and precise complex expression patterns exhibited by developmental genes.
authors.affiliation: Sars Centre for Marine Molecular Biology, University of Bergen, 5008 Bergen, Norway.
authors.forename: Pavla
authors.initials: P
authors.lastname: Navratilova
authors.forename: David
authors.initials: D
authors.lastname: Fredman
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Hawkins
authors.forename: Katherine
authors.initials: K
authors.lastname: Turner
authors.forename: Boris
authors.initials: B
authors.lastname: Lenhard
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Becker
mesh_terms: D000818:Animals; D001665:Binding Sites; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050436:Regulatory Elements, Transcriptional; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes; D015027:Zebrafish / Q000033:anatomy & histology / Q000502:physiology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D055748:SOXB1 Transcription Factors; D029961:Zebrafish Proteins