Cecilia L. Winata1,#, Igor Kondrychyn2,#,*, Vibhor Kumar3, Kandhadayar G. Srinivasan4, Yuriy Orlov5,
Ashwini Ravishankar1, Shyam Prabhakar3, Lawrence W. Stanton6, Vladimir Korzh2,
1 Human Genetics, Genome Institute of Singapore, Singapore
2 Fish Developmental Biology, Institute of Molecular and Cell Biology, Singapore
3 Computational and Mathematical Biology, Genome Institute of Singapore, Singapore
4 Functional Genomics Core, Singapore Immunology Network, Singapore
5 Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
6 Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore
* Current address: National Centre for Biological Sciences, Bangalore, India.
# These authors contributed equally to this work.
Published in PLoS Genetics on 31 October 2013.
The Zic3 transcription factor regulates early embryonic patterning, and the loss of its function leads to defects in left-right body asymmetry. Previous studies have only identified a small number of Zic3 targets, which renders the molecular mechanism underlying its activity insufficiently understood. Utilizing two genomics technologies, next generation sequencing and microarray, we profile the genome-wide binding sites of Zic3 and identified its target genes in the developing zebrafish embryo. Our results show that Zic3 regulates its target genes predominantly through regulatory elements located far from promoters. Among the targets of Zic3 are the Nodal and Wnt pathways known to regulate gastrulation and left-right body asymmetry, as well as neural pre-pattern genes regulating proliferation of neural progenitors. Using enhancer activity assay, we further show that genomic regions bound by Zic3 function act as enhancers. Our study provides a genome-wide view of the regulatory landscape of Zic3 and its changes during vertebrate development.
Figure Legend: Zic3-regulated genes in the Nodal and Wnt signaling pathways.
Schematic diagram of the Nodal/TGF-β and Wnt signaling pathways generated by the Ingenuity Pathway Analysis Software. Genes differentially regulated by Zic3 are shown in colour – red for upregulation and green for downregulation of their expression patterns in the microarray data.
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