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C. H. Pratt, R. Vadigepalli, P. Chakravarthula, G. E. Gonye, N. J. Philp, G. B. Grunwald; Transcriptional Regulatory Network Analysis of RPE Cells During Epithelial-Mesenchymal Transitions. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1934.
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Phenotypic transformation of retinal pigment epithelial (RPE) cells contributes to the onset and progression of ocular proliferative disorders such as proliferative vitreoretinopathy (PVR). The formation of epiretinal membranes in PVR may involve an epithelial-mesenchymal transformation (EMT) of RPE cells as part of an aberrant wound healing response. While the underlying mechanism remains unclear, this likely involves changes in RPE cell gene expression under the control of specific transcription factors (TFs). Thus, the purpose of the present study was to identify TFs that may play a role in this process.
The regulatory regions of genes that are differentially regulated during EMT of RPE cells were subjected to a computational analysis using the Promoter Analysis and Interaction Network Toolset (PAINT) that identified statistically over-represented transcription response elements (TREs). These TREs were utilized to construct regulatory region models of the two differentially regulated gene sets. The validity of these models was tested using RT-PCR to detect differential expression of the corresponding TF mRNAs during RPE cell differentiation.
The PAINT analysis and model building revealed a subset of TREs that may be involved in the regulation of RPE cell genes during EMT. The differential expression of the TFs predicted by the models was successfully verified by RT-PCR analysis and include the following: Oct-1, HNF-1, SMAD3, TFE, Core Binding Factor, GATA-1, IRF, NKX3A, SREBP-1 and LEF-1. While not previously analyzed in the context of RPE cells, the TFs identified in the present study can be categorized with respect to other cell types into three groups that include (1) TFs not previously associated with EMT; (2) TFs that, while not previously known to directly affect EMT, have been shown to regulate cellular processes that are components of EMT, and (3) TFs previously shown to directly affect EMT principally in other cell types.
These studies applied computational modeling along with biochemical verification to identify biologically relevant TFs that are likely to regulate cell phenotype and pathological changes in RPE in response to diseases or trauma.
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