Many thanks are due to Pete Jozsi and his excellent EpiGenie web site for introducing CH3 BioSystems to the Tweetogospheric world of sci-social media. Observations, random ideas, topical reviews, bald speculations and various other brainstorms involving protein methylation will begin appearing here throughout 2011 and hopefully beyond. To start things off, we are re-posting our first contribution to the EpiGenie web site into our very own electron-rich user interface (see below).
Please comment, and remember to visit EpiGenie for updates on all things epigenetic!
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Epigenetics is the study of heritable changes of phenotype that occur without alteration of the genome’s nucleotide sequence. Epigenetic regulation is too often viewed as DNA modification, typically methylation, or chromatin remodeling by ATP-dependent protein complexes. But, besides DNA methylation and chromatin reorganization, it turns out that the post-translational modification of proteins is also extremely 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 and Stallcup, 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 2000, 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.
For example, long-term changes in offspring phenotype are associated with dietary restrictions (Kappeler and Meaney, 2010) and reduced caloric intake (Vaquero and Reinberg, 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, PPAR co-activator γ 1α and others) are substrates for PRMTs. Recently the arginine methylation of C/EBPβ, a transcription factor that regulates genes involved in metabolism, was found to regulate the interaction of C/EBPβ with epigenetic gene regulatory protein complexes during cell differentiation (Kowenz-Leutz et al., 2010). DNA methylation-mediated silencing actions may further be regulated by arginine methylation of MBD2, a methyl-DNA binding protein (Tan and Nakielny, 2006). The methylation of MBD2 decreases binding to methyl-DNA and histone deacetylases, thus decreasing transcriptional repression.
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 et al., 2010), and piwi proteins, which suppress mobile genetic elements in the germ cells of multi-cellular animals (Vagin et al., 2009).
Lastly, we have the example of cell signaling via arginine methylated estrogen receptor α (ERα). 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 et al., 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. If you know of other examples, have comments or questions, please post any input here. CH3 will welcome any opportunity to spread interest and further understanding of protein arginine methylation and its relationships to biology and biomedical science.
