Functional inactivation of menin, encoded by the MEN1 gene, causes the inherited multiple endocrine neoplasia type 1 (MEN1) syndrome and some but not all sporadic pancreatic endocrine tumors. Therefore, unraveling molecular events upstream or downstream of menin could point to other causative genes and/or regulatory events responsible for such tumor types. Menin resides in a histone methylating protein complex that trimethylates histone 3 at lysine 4 (H3K4me3), an epigenetic mark for active gene expression. Therefore, we have determined a genome-wide map of menin-dependent H3K4me3 (using ChIP-Seq) and menin-dependent gene-expression program in wild-type (WT) and menin-null mouse embryonic stem cells (ESCs) and in pancreatic islet-like endocrine cells (PILECs), which we derived from WT and menin-null mouse ESCs through in vitro differentiation. We found menin-dependent H3K4me3 specifically targeting the Meg3 gene in mouse ESCs, and all four Hox loci in differentiated PILECs. Gene expression from the Meg3 locus and from all of the four Hox loci was abolished in menin-null cells. Both Meg3 and Hox loci have been implicated in MEN1-like sporadic tumors: MEG3 in pituitary tumors, and HOX in parathyroid tumors. Our data suggest that these genes with menin-dependent H3K4me3 could be relevant players in the tumorigenesis of pancreatic endocrine cells. Furthermore, our work shows that menin-null mouse ESCs could also be differentiated in vitro into islet-like endocrine cells, underscoring the utility of menin-null ESC-derived specialized cell types for genome-wide analyses studies. Proper tissue differentiation is dependent upon a precise control over the coordination between cell cycle events and the expression and activity of tissue-specifying factors. This type of coordination could go awry to result in tumor formation. Our current efforts are directed towards studying novel and implicated factors associated with endocrine tumorigenesis for menin-regulated transcriptional, post-transcriptional, protein:protein interaction, and sub-cellular localization events: 1) Cell cycle regulators, particularly cyclin-dependent kinases and their inhibitors, 2) Endocrine pancreas differentiation factors, and 3) Genes at the MEG3 and HOX loci.
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