ZFIN ID: ZDB-PUB-081218-15
Systematic human/zebrafish comparative identification of cis-regulatory activity around vertebrate developmental transcription factor genes
Navratilova, P., Fredman, D., Hawkins, T.A., Turner, K., Lenhard, B., and Becker, T.S.
Date: 2009
Source: Developmental Biology   327(2): 526-540 (Journal)
Registered Authors: Becker, Thomas S., Hawkins, Tom, Navratilova, Pavla
Keywords: cis-regulation, transcription, ELP4, IMMP1L, RCN1, WT1, CTCF insulator, Tol2 transposon
MeSH Terms:
  • Animals
  • Binding Sites
  • Eye Proteins/genetics
  • Eye Proteins/metabolism*
  • Gene Expression Regulation, Developmental*
  • Homeodomain Proteins/genetics
  • Homeodomain Proteins/metabolism*
  • Humans
  • Mice
  • Paired Box Transcription Factors/genetics
  • Paired Box Transcription Factors/metabolism*
  • Regulatory Elements, Transcriptional*
  • Repressor Proteins/genetics
  • Repressor Proteins/metabolism*
  • SOXB1 Transcription Factors/genetics
  • SOXB1 Transcription Factors/metabolism*
  • Transgenes
  • Zebrafish/anatomy & histology
  • Zebrafish/physiology*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 19073165 Full text @ Dev. Biol.
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.