The Cis-regulatory Logic of the Mammalian Photoreceptor Transcriptional Network
Open Access
- 25 July 2007
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 2 (7) , e643
- https://doi.org/10.1371/journal.pone.0000643
Abstract
The photoreceptor cells of the retina are subject to a greater number of genetic diseases than any other cell type in the human body. The majority of more than 120 cloned human blindness genes are highly expressed in photoreceptors. In order to establish an integrative framework in which to understand these diseases, we have undertaken an experimental and computational analysis of the network controlled by the mammalian photoreceptor transcription factors, Crx, Nrl, and Nr2e3. Using microarray and in situ hybridization datasets we have produced a model of this network which contains over 600 genes, including numerous retinal disease loci as well as previously uncharacterized photoreceptor transcription factors. To elucidate the connectivity of this network, we devised a computational algorithm to identify the photoreceptor-specific cis-regulatory elements (CREs) mediating the interactions between these transcription factors and their target genes. In vivo validation of our computational predictions resulted in the discovery of 19 novel photoreceptor-specific CREs near retinal disease genes. Examination of these CREs permitted the definition of a simple cis-regulatory grammar rule associated with high-level expression. To test the generality of this rule, we used an expanded form of it as a selection filter to evolve photoreceptor CREs from random DNA sequences in silico. When fused to fluorescent reporters, these evolved CREs drove strong, photoreceptor-specific expression in vivo. This study represents the first systematic identification and in vivo validation of CREs in a mammalian neuronal cell type and lays the groundwork for a systems biology of photoreceptor transcriptional regulation.Keywords
This publication has 71 references indexed in Scilit:
- A typology of photoreceptor gene expression patterns in the mouseProceedings of the National Academy of Sciences, 2007
- In vivo enhancer analysis of human conserved non-coding sequencesNature, 2006
- Genome-wide computational prediction of transcriptional regulatory modules reveals new insights into human gene expressionGenome Research, 2006
- The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cellsNature Genetics, 2006
- A Hybrid Photoreceptor Expressing Both Rod and Cone Genes in a Mouse Model of Enhanced S-Cone SyndromePLoS Genetics, 2005
- Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomesGenome Research, 2005
- Transcriptional Control in the Segmentation Gene Network of DrosophilaPLoS Biology, 2004
- Genomic Analysis of Mouse Retinal DevelopmentPLoS Biology, 2004
- Transcription regulation and animal diversityNature, 2003
- Comprehensive Analysis of Photoreceptor Gene Expression and the Identification of Candidate Retinal Disease GenesCell, 2001