Identification of regulatory targets of tissue-specific transcription factors: application to retina-specific gene regulation.
Identification of tissue-specific gene regulatory networks can yield insights into the molecular basis of a tissue's development, function and pathology. Here, we present a computational approach designed to identify potential regulatory target genes of photoreceptor cell-specific transcription factors (TFs). The approach is based on the hypothesis that genes related to the retina in terms of expression, disease and/or function are more likely to be the targets of retina-specific TFs than other genes. A list of genes that are preferentially expressed in retina was obtained by integrating expressed sequence tag, SAGE and microarray datasets. The regulatory targets of retina-specific TFs are enriched in this set of retina-related genes. A Bayesian approach was employed to integrate information about binding site location relative to a gene's transcription start site. Our method was applied to three retina-specific TFs, CRX, NRL and NR2E3, and a number of potential targets were predicted. To experimentally assess the validity of the bioinformatic predictions, mobility shift, transient transfection and chromatin immunoprecipitation assays were performed with five predicted CRX targets, and the results were suggestive of CRX regulation in 5/5, 3/5 and 4/5 cases, respectively. Together, these experiments strongly suggest that RP1, GUCY2D, ABCA4 are novel targets of CRX.
Qian
Jiang
J
Wilmer Institute, Johns Hopkins University School of Medicine Baltimore, MD 21287, USA. jiang.qian@jhmi.edu
Esumi
Noriko
N
Chen
Yangjian
Y
Wang
Qingliang
Q
Chowers
Itay
I
Zack
Donald J
DJ
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors; D001499:Bayes Theorem; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005136:Eye Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012160:Retina / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; C485736:Nr2e3 protein, mouse; C084884:Nrl protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors; C109288:cone rod homeobox protein