DescriptionMultiple Endocrine Neoplasia type 1 (MEN1) is a familial syndrome manifest by the formation of tissue-specific cancers with global DNA hypermethylation in affected tissues. The mechanisms underlying this selective tumorigenesis are not well known and we hypothesize the involvement of tissue-specific factors. We utilize a comprehensive approach to identify such factors driving the tissue- selective tumor formation. We have performed a systematic ChIP-Seq and RNA- Seq analysis of MEN1-associated cell types, followed by data mining using an integrated bioinformatics approach. Subsequently, we identified Pax5 as a novel tissue-specific factor that mediates the recruitment of a DNA methylation activator shown to drive the tumorigenesis in MEN1 Syndrome. These findings provide insight into a novel mechanism of MEN1-associated tissue-specific tumorigenesis. These findings may be relevant to the study of other tumor suppressor genes associated with a tissue restricted tumor phenotype.