Genome-wide analysis of the coactivator-associated arginine methyltransferase CARM1 in breast cancer cells

The family of protein arginine methyltransferases (PRMTs) is involved in many different cellular processes. One of the best-characterized PRMT members, the coactivator-associated arginine methyltransferase CARM1/PRMT4 has been shown to function as a coactivator for both nuclear receptor and other signal-activated transcriptional pathways. Its recruitment by transcriptional coactivators induces histone H3 arginine methylation, leading to gene activation. Additionally, arginine methylation by CARM1 has been involved with other aspects of gene expression, including regulation of coactivator complex assembly and RNA binding protein regulation. However, it remains poorly understood how CARM1 functions in vivo to coordinately modify histories and regulate different processes during the gene expression pathway. To understand the mechanisms by which CARM1 functions, we sought to define the genomic binding sites of CARM1. Here we describe the genome-wide localization of CARM1 in human breast cancer cells by chromatin immunoprecipitation coupled with microarray analysis (ChIP-on-chip). The unbiased identification of DNA sites occupied by CARM1 reveals that this histone-modifying enzyme occupies highly conserved genomic regions occurring predominately at the transcription starts site of genes. Many of the target promoters represent classes of genes associated with cellular proliferation, including regulation of the cell cycle, metabolism and development. Interestingly, we find that binding occurs at specific sites independently of estrogen stimulation. We identified many novel CARM1 targets as well as putative transcription factors that share CARM1 binding sites. Together, this data suggests a more global role for CARM1 in the positive regulation of transcription. In summary, these results provide new gene targets of regulation by CARM1 in breast cancer cells and suggest new mechanisms for this regulation. Furthermore, they implicate CARM1 in the control of cellular proliferation through the activation of genes involved with growth and cell cycle entry. Overall, this work has contributed to our understanding of the roles of arginine methylation and the cellular function of CARM1.