The estrogen receptor (ER) regulates gene expression by either direct binding to estrogen response elements or indirect tethering to other transcription factors on promoter targets. To identify these promoter sequences, we conducted a genome-wide screening with a novel microarray technique called ChIP-on-chip. A set of 70 candidate ER&alpha loci were identified and the corresponding promoter sequences were analyzed by statistical pattern recognition and comparative genomics approaches. We found mouse counterparts for 63 of these loci, and classified 42 (67%) as direct ER targets using classification and regression tree (CART) statistical model, which involves position weight matrix and human-mouse sequence similarity scores as model parameters. The remaining genes were considered to be indirect targets. To validate this computational prediction, we conducted an additional ChIP-on-chip assay that identified acetylated chromatin components in active ER promoters. Of 27 loci upregulated in an ER&alpha positive breast cancer cell line, 20 having mouse counterparts were correctly predicted by CART. This integrated approach therefore sets a paradigm in which the iterative process of model refinement and experimental verification will continue until an accurate prediction of promoter target sequences is derived.

Dr. Victor Jin is a postdoctoral fellow of Bioinformatics and Computational Biology at The Ohio State University. He received the Ph.D degree from Queen's University in Kingston, ON in 2000 and an M.Sc. in Computer Science from the University of Ottawa in 2002. His reseasrch interests are in developing computational approaches (software tools, algorithms and statistical model) for the identification and characterization of genomic regulatory elements and networks and testing them experimentally by the chromatin immunoprecipitation microarray. He is interested in understanding the pathways of hormone receptors related to breast cancer such as the estrogen receptor, the progesterone receptor, and prostate cancer such as the androgen receptor. [an error occurred while processing this directive]