The product of the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor 
gene, menin, is an integral component of MLL1/MLL2 histone methyltransferase 
complexes specific for Lys4 of histone H3 (H3K4). We show that menin is a 
transcriptional coactivator of the nuclear receptors for estrogen and vitamin D. 
Activation of the endogenous estrogen-responsive TFF1 (pS2) gene results in 
promoter recruitment of menin and in elevated trimethylation of H3K4. Knockdown 
of menin reduces both activated TFF1 (pS2) transcription and H3K4 
trimethylation. In addition, menin can directly interact with the estrogen 
receptor-alpha (ERalpha) in a hormone-dependent manner. The majority of 
disease-related MEN1 mutations prevent menin-ERalpha interaction. Importantly, 
ERalpha-interacting mutants are also defective in coactivator function. Our 
results indicate that menin is a critical link between recruitment of histone 
methyltransferase complexes and nuclear receptor-mediated transcription.