Transcriptional Regulation of Estrogen Receptor (ER) by CARM1

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DESCRIPTION (provided by applicant): CARM1, coactivator associated arginine (R) methyltransferase 1, is involved in the activation of a number of transcriptional factors, including NF-?B, p53, E2F1 and steroid receptors, among which transcriptional activation of estrogen receptors (ERs) by CARM1 is best characterized. CARM1 methylates histone H3 at R17, and this methylation correlates with activation of the ER-target gene pS2. Loss of CARM1 leads to abrogation of the estrogen response and reduction in expression of some ER-target genes. We recently identified a CARM1-associated complex, nucleosomal methylation activator complex (NuMAC), which includes multiple components of SWI/SNF chromatin remodeling complex. SWI/SNF has also been implicated in ER-mediated transcriptional activation, and loss of SWI/SNF function is common in cancer progression. Interestingly, we have recently found that CARM1 can be phosphorylated in vivo and that its phosphorylation inhibits its histone methyltransferase (HMT) activity. We have generated phosphorylation-defective mutants of CARM1, which provide us a powerful tool to investigate the molecular mechanism of the regulation of ER-signaling by the CARM1 complex. This study is proposed to further understand the mode of transcriptional regulation and the cellular signaling of CARM1 in the context of ER. Given the surge of interest in histone arginine methylation in transcriptional regulation and the incorporation of two enzymatic activities, HMT and ATP-dependent remodeling, in the ER coactivator complex, our long-term objectives are to analyze the molecular underpinnings of ER transcriptional regulation by the CARM1 complex and to determine its functional relevance to the development of breast cancer. Our central hypothesis is that CARM1 and its associated enzymatic activities are important in regulating a subset of ER-target genes. CARM1 plays a central role in signal transduction, which is regulated by upstream cellular pathways and encodes a methyl-mark on histones to lead to the downstream transcription activation. Here I outline a series of experiments using biochemical, cell-based, and genomic approaches to study: (a) the molecular mechanism of the regulation of ER-target gene expression by CARM1 and SWI/SNF; (b) the effect of CARM1 phosphorylation on ER-dependent transcription and upstream signaling pathways and that lead to CARM1 inactivation; and (c) the downstream cellular effects of estrogen-dependent histone arginine methylation. These studies will provide a new understanding of the mechanism and functional significance of histone arginine methylation in ER-regulated processes.