the cis-regulatory logic of the mammalian photoreceptor transcriptional network哺乳动物的感光转录的基因工程逻辑网络.pdf

The Cis-regulatory Logic of the Mammalian Photoreceptor Transcriptional Network 1 1 1 1 2 1 Timothy H.-C. Hsiau , Claudiu Diaconu , Connie A. Myers , Jongwoo Lee , Constance L. Cepko *, Joseph C. Corbo * 1 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America, 2 Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America 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 generalit