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The Journal of Neuroscience, June 20, 2007, 27(25):6729-6739; doi:10.1523/JNEUROSCI.0091-07.2007

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Cellular/Molecular
A New Binding Motif for the Transcriptional Repressor REST Uncovers Large Gene Networks Devoted to Neuronal Functions

Stefanie J. Otto,¹ Sean R. McCorkle,² John Hover,¹ Cecilia Conaco,¹ Jong-Jin Han,¹ Soren Impey,³ Gregory S. Yochum,³ John J. Dunn,² Richard H. Goodman,³ and Gail Mandel¹

¹Howard Hughes Medical Institute, Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, New York 11794, ²Department of Biology, Brookhaven National Laboratory, Upton, New York 11973, and ³Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239

Correspondence should be addressed to Dr. Gail Mandel at her present address: Howard Hughes Medical Institute, Vollum Institute, Oregon Health and Science University, Portland, OR 97239. Email: mandelg{at}ohsu.edu

The repressor element 1 (RE1) silencing transcription factor (REST) helps preserve the identity of nervous tissue by silencing neuronal genes in non-neural tissues. Moreover, in an epithelial model of tumorigenesis, loss of REST function is associated with loss of adhesion, suggesting the aberrant expression of REST-controlled genes encoding this property. To date, no adhesion molecules under REST control have been identified. Here, we used serial analysis of chromatin occupancy to perform genome-wide identification of REST-occupied target sequences (RE1 sites) in a kidney cell line. We discovered novel REST-binding motifs and found that the number of RE1 sites far exceeded previous estimates. A large family of targets encoding adhesion proteins was identified, as were genes encoding signature proteins of neuroendocrine tumors. Unexpectedly, genes considered exclusively non-neuronal also contained an RE1 motif and were expressed in neurons. This supports the model that REST binding is a critical determinant of neuronal phenotype.

Key words: REST; transcription; serial analysis of chromatin occupancy; binding motif; synaptic transmission; neuroendocrine tumors

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Received Jan. 9, 2007; revised April 20, 2007; accepted May 14, 2007.

Correspondence should be addressed to Dr. Gail Mandel at her present address: Howard Hughes Medical Institute, Vollum Institute, Oregon Health and Science University, Portland, OR 97239. Email: mandelg{at}ohsu.edu

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