Histone methylation and transcriptional by the menin tumor suppresor

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Project Summary: Menin is encoded by the MEN1 gene and was initially identified because of its involvement in Multiple Endocine Neoplasia (MEN1), an autosomal dominant cancer syndrome. The MEN1 gene is expressed in most cell types throughout development, however mutation or deletion of menin typically results in tumorigenesis within the pituitary, parathyroid, lungs and enteropancreatic tissues. Recently, it has been shown that menin functions in collaboration with Mixed Leukemia Lineage (MLL) and MLL2 protein complexes to regulate the expression of the cyclin-dependent kinase inhibitors p18 and p27. The activation of these genes was dependent upon the histone methyltransferase activity of the MLL/MLL2 protein complexes. The research objective is to examine the role of menin in the recruitment of MLL/MLL2 complexes to target genes and understand how these complexes regulate gene expression. To investigate how menin functions as a tumor suppressor within endocrine tissue, we will use a Men1+/- mouse model that develops an array of tumors that is comparable to what is observed in humans. Gene expression profiling, chromatin immunoprecipitation and immunopurification assays will be performed to establish a model for menin mediated gene activation within the panceatic islet. Specific Aims: 1. Identify transcriptional target genes of menin in mouse pancreatic islets. 2. Determine the role of the menin-MLL/MLL2 complexes in modulating chromatin structure and facilitating gene activation within the pancreatic (3cells. 3. Investigate the post-translational modifications of menin and their effects on complex formation and cellular function. Cancer Relevance: At this time, very little is known about how menin functions as a tumor suppressor or why endocrine tissue is susceptible to neoplasia when menin is mutated or absent. These studies will provide a foundation for studying the molecular mechanisms mediated by menin and MLL/MLL2 protein complexes in pancreatic gene expression. The long-term goal of these studies are to identify therapeutic targets within the cell that could be specifically inhibited to control cellular proliferation.