CARM1 and Regulation of the Estrogen Receptor
Several forms of post-translational modification regulate protein activities. Recently, protein methylation by CARM1 (coactivator-associated arginine methyltransferase 1) has been observed to play a key role in transcriptional regulation. CARM1 associates with the p160 class of transcriptional coactivators involved in gene activation by steroid hormone family receptors. CARM1 also interacts with CBP/p300 transcriptional coactivators involved in gene activation by a large variety of transcription factors, including steroid hormone receptors and CEBP. One target of CARM1 is the core histones H3 and H4, which are also targets of the histone acetylase activity of CBP/p300 coactivators. Recruitment of CARM1 to the promoter region by binding to coactivators increases histone methylation and makes promoter regions more accessible for transcription. Another target of CARM1 methylation is a coactivator it interacts with, CBP. Methylation of CBP by CARM1 blocks CBP from acting as a coactivator for CREB and redirects the limited CBP pool in the cell to be available for steroid hormone receptors. Other forms of post-translational protein modification such as phosphorylation are reversible in nature, but as of yet a protein demethylase is not known. The methylation activity of CARM1 modulates the activity of specific transcriptional regulators. CARM1 acts as a coactivator for the myogenic transcription factor Mef2c, and is necessary for normal muscle cell differentiation. The estrogen receptor is another transcription factor that uses CARM1 as one of several coactivators, acting synergistically with CBP through the Grip1 member of the p160 family of coactivators. The interaction of estrogen receptor with various ligand-dependent coactivators may produce the tissue selective response of some estrogen receptor ligands like tamoxifen.
Contributor: Kosi Gramatikoff, PhD
REFERENCES: Bauer UM, Daujat S, Nielsen SJ, Nightingale K, Kouzarides T. Methylation at arginine 17 of histone H3 is linked to gene activation. EMBO Rep. 2002 Jan;3(1):39-44. Chen SL, Loffler KA, Chen D, Stallcup MR, Muscat GE. The coactivator-associated arginine methyltransferase is necessary for muscle differentiation: CARM1 coactivates myocyte enhancer factor-2. J Biol Chem. 2002 Feb 8;277(6):4324-33. Chen, D. et al. (1999) Regulation of transcription by a protein methyltransferase. Science 284(5423), 2174-7 Koh SS, Li H, Lee YH, Widelitz RB, Chuong CM, Stallcup MR. Synergistic coactivator function by coactivator-associated arginine methyltransferase (CARM) 1 and beta-catenin with two different classes of DNA-binding transcriptional activators. J Biol Chem. 2002 Jul 19;277(29):26031-5. Ma, H. et al. (2001) Hormone-dependent, CARM1-directed, arginine-specific methylation of histone H3 on a steroid-regulated promoter. Curr. Biol. 11(24), 1981-5 McDonnell DP, Norris JD. Connections and regulation of the human estrogen receptor. Science. 2002 May 31;296(5573):1642-4. Review. Xu, W. et al. (2001) A transcriptional switch mediated by cofactor methylation. Science 294(5551), 2507-11
