Namgyu Lee has participated in the experimental part of this project and she is a co-first author of the under-going manuscript. RE-1 silencing transcription factor (REST) is a transcriptional repressor with a role in regulating gene expression through binding to repressor element 1. We identified REST/NRSF-interacting proteins by proteomics-based analyses using the complementary mass spectrometry approach. Our interactome revealed 204 REST-interacting proteins. Among those proteins, nuclear proteins were mostly enriched reflecting nuclear localization of REST. The interaction networks of interactome indicated biological processes associated with mRNA processing, chromatin organization and transcription. Interactions of ALYREF, HnRNP M, HnRNP Q, NPM1, NCL, PARP1, HDAC5, TRIM28 and HMGA1 with REST were confirmed by co-immunoprecipitation. Using public microarray dataset, a highly significant overlaps were observed in differentially expressed transcripts following knockdown of REST and interacting proteins such as HDAC5, HMGA1 and TRIM28, suggesting that the REST might cross-talk with those transcription regulators to regulate transcription of shared target genes. Our interactomic study of REST implies novel cross-talks with transcription regulators by its associations with interacting proteins.