Genome-Wide Analysis of Menin Binding Provides Insights into MEN1 Tumorigenesis

Abstract

Multiple endocrine neoplasia type I (MEN1) is a familial cancer syndrome characterized primarily by tumors of multiple endocrine glands. The gene for MEN1 encodes a ubiquitously expressed tumor suppressor protein called menin. Menin was recently shown to interact with several components of a trithorax family histone methyltransferase complex including ASH2, Rbbp5, WDR5, and the leukemia proto-oncoprotein MLL. To elucidate menin's role as a tumor suppressor and gain insights into the endocrine-specific tumor phenotype in MEN1, we mapped the genomic binding sites of menin, MLL1, and Rbbp5, to approximately 20,000 promoters in HeLa S3, HepG2, and pancreatic islet cells using the strategy of chromatin-immunoprecipitation coupled with microarray analysis. We found that menin, MLL1, and Rbbp5 localize to the promoters of thousands of human genes but do not always bind together. These data suggest that menin functions as a general regulator of transcription. We also found that factor occupancy generally correlates with high gene expression but that the loss of menin does not result in significant changes in most transcript levels. One exception is the developmentally programmed transcription factor, HLXB9, which is overexpressed in islets in the absence of menin. Our findings expand the realm of menin-targeted genes several hundred-fold beyond that previously described and provide potential insights to the endocrine tumor bias observed in MEN1 patients. In multiple endocrine neoplasia type I, absence of the nuclear factor menin gives rise to endocrine tumors by a mechanism that is poorly understood. Using state-of-the-art genome-wide chromatin-immunoprecipitation coupled with microarray analysis technology, this paper significantly enlarges our understanding of the role of menin by greatly extending the number of gene targets where menin binds. The authors show that while menin frequently colocalizes with a protein complex that modifies chromatin structure, menin can also bind to many other promoters by an alternative mechanism. They also present data that potentially implicate one of the menin target genes, HLXB9, in the endocrine specificity of tumorigenesis in multiple endocrine neoplasia, type 1. Further experiments to confirm the role of HLXB9 in tumorigenesis are necessary and may help explain how the loss of a ubiquitously expressed tumor suppressor gene can give rise to tumors in specific tissues.