The completion of whole genome sequencing projects has provided the genetic instructions of life. However, whereas the identification of gene coding regions has progressed, the mapping of transcriptional regulatory motifs has moved more slowly. To understand how distinct expression profiles can be established and maintained, a greater understanding of these sequences and their trans-acting factors is required. Herein we have used a combined in silico and biochemical approach to identify binding sites [repressor element 1͞neuron-restrictive silencer element (RE1͞NRSE)] and potential target genes of RE1 silencing transcription factor͞neu-ron-restrictive silencing factor (REST͞NRSF) within the human, mouse, and Fugu rubripes genomes. We have used this genomewide analysis to identify 1,892 human, 1,894 mouse, and 554 Fugu RE1͞NRSEs and present their location and gene linkages in a searchable database. Furthermore, we identified an in vivo hierarchy in which distinct subsets of RE1͞NRSEs interact with endogenous levels of REST͞NRSF, whereas others function as bona fide transcriptional control elements only in the presence of elevated levels of REST͞NRSF. These data show that individual RE1͞NRSE sites interact differentially with REST͞NRSF within a particular cell type. This combined bioinformatic and biochemical approach serves to illustrate the selective manner in which a transcription factor interacts with its potential binding sites and regulates target genes. In addition, this approach provides a unique whole-genome map for a given transcription factor-binding site implicated in establishing specific patterns of neuronal gene expression.

Protein complexes that contain chromatin-modifying enzymes have an important role in regulating gene expression. Recent studies have shown that a single transcription factor, the repressor element 1-silencing transcription factor (REST), can act as a hub for the recruitment of multiple chromatin-modifying enzymes, uncovering interdependencies among individual enzymes that affect gene regulation. Research into the function of REST and its corepressors has provided novel insight into how chromatin-modifying proteins cooperate, and how alterations in this function cause disease. These mechanisms will be relevant to the combinatorial functioning of modular transcriptional regulators that work together to regulate a common promoter; they should also identify targets for potential therapies for a range of human diseases.

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