While epigenetic mechanisms like DNA methylation and chromatin remodeling get most of the attention, more is being learned everyday about other important mechanisms that are just now starting to get their share of the limelight. In this article contributed by John Aletta at CH3 Biosystems, he explains how protein arginine methylation is also a key player in epigenetics.
Protein Methylation: Over-looked, But Not Forgotten
An often over-looked means of epigenetic regulation is post-translational modification of proteins that are important for gene expression. In particular, the rapidly expanding field of protein arginine methylation is noteworthy in several instances for affecting gene expression through the placement of methyl marks on many different proteins in addition to the histones (Lee, Y-H and Stallcup, MR Molec. Endocrinol 2009).
There may be rather broad relevance of this post-translational modification for human biology ranging from inherited dietary preferences to carcinogenesis. As long ago as 2001, the Stallcup lab at USC discovered that protein arginine methyltransferases (PRMTs) serve as co-activators. The substrates for methylation in the early studies were found to be histone proteins, but since then everything from DNA binders, elongation factors, signaling molecules and many other proteins affecting gene expression exhibit altered functions and/or cellular locations as a result of arginine methylation.
Protein Methylation & Metabolism
For example, long-term changes in offspring phenotype are associated with dietary restrictions, adverse intrauterine conditions (Pinney SE & Simmons RA, Trends in Endocrinology & Metabolism 2010) and reduced caloric intake (Vaquero and Reinberg, Genes & Deleopment 2009). The precise mechanism(s) of the epigenetic modifications observed are unresolved, but clearly are secondary to changes in the gene expression of metabolic intermediates. Of course, DNA methylation and differential access of chromatin remodelers based on histone methylation have been considered, but arginine methylation of other nuclear proteins may also play a role. Many well-known transcriptional co-regulators (e.g. CBP/p300, steroid receptor co-activator/p160, PPARg co-activator 1a and others) are substrates for PRMTs. Recently the arginine methylation of C/EBPß, a transcription factor that regulates genes involved in metabolism, was found to regulate the interaction of C/EBPß with epigenetic gene regulatory protein complexes during cell differentiation (Kowenz-Leutz E et al., EMBO J 2010). DNA methylation-mediated silencing actions may further be regulated by arginine methylation of MBD2, a methyl-DNA binding protein (Tan and Nakielny, Molecular Cell Biology, 2006). The methylation of MBD2 decreases binding to methyl-DNA and histone deacetylases, thus decreasing transcriptional repression.
Link to Germ Cell Development
The fidelity of genetic inheritance is fundamentally dependent on proper germ cell development. Here again, current leading edge research casts a spotlight on PRMTs and the substrates upon which methyl marks are placed. The enzymes and methylproteins are emerging as critically important molecular determinants of proper germ cell development. Recent examples are the arginine methylation of the RNA helicase, vasa and its vertebrate homologs (Kirino, Y. et al., JBC 2010), and piwi proteins, which suppress mobile genetic elements in the germ cells of multi-cellular animals (Vagin VV et al., Genes & Development, 2009).
Cell Signaling Mechanisms
Lastly, we have the example of cell signaling via arginine methylated estrogen receptor a (ERa). The methylation of ERa is required for the extra-nuclear function of the receptor to signal to downstream Src/FAK and p85/Akt for proliferative and survival actions. Additional immunohistochemical data from a cohort of breast cancer patients also provide implications for potential epigenetic mechanisms of tumorigenesis (Le Romancer, M. et al., Steroids 2010).
These few examples just barely scratch the surface of the potential involvement of protein arginine methylation in the epigenetics of human health and disease.