We have generated targeted disruptions of the arginine methyltransferase genes in the mouse in the hope of unmasking cellular and tissue-specific roles for this post-translational modification. One of the arginine methyltransferases we have knocked-out is CARM1. This enzyme associates with the p160 family of nuclear hormone receptor coactivators. Using both knockout cell lines and embryos, we have shown the critical nature of CARM1 in estrogen responsive gene expression. To identify the genes that recruit the co-activator activity of CARM1, transcriptome analysis using both SAGE and cDNA arrays is being performed on knockout and wildtype embryos. The targeted CARM1 allele is floxed, thus allowing conditional knockouts to be performed. We are currently tissue-specifically ablating CARM1 function in the mammary gland and in early T cell development, using the Cre recombinase-mediated approach. In addition, we are crossing the CARM1-/+ mice with p300-/+ mice to investigate, at the genetic level, the cross-talk between protein methylation and acetylation. Knockout mouse model are currently being developed for additional PRMTs.