In a past contribution from CH3 BioSystems, evidence for the role of protein methylation as a key epigenetic regulator in addition to DNA methylation was described. Since protein arginine methylation can produce important direct regulatory control over gene expression, it shouldn’t be surprising that it may also play a role in mitotic bookmarking, the latest epigenetic mechanism observed to regulate gene expression during normal cell development and carcinogenesis. Mitotic bookmarking is a heritable form of epigenetic control that maintains cell identity following mitosis through a combination of histone modifications, DNA methylation and the retention of specific transcription factors at specific phenotypic promoter sites.
An excellent recent review of bookmarking from Gary Stein’s lab at U. Mass. Cancer Center came out last summer in Nature Reviews Genetics. The Opinion piece does not directly reference protein arginine methylation, but it is intriguing that many of the effector molecules that carry out the bookmarking functions described in the review turn out to be methylarginine-modified proteins. A few brief provocative examples are offered below to stimulate some brainstorming. To understand the mechanism of the gene expression control exerted by bookmarking, it’s necessary to recognize that the compartmentalization and focal organization of protein complexes in nuclear microenvironments depends on diverse elements, such as RNA Pol I and Pol II, scaffold proteins, splicing factors and nuclear receptors.
Keeping Tabs On the Evidence
Dynamic nuclear micro-domains tend to be organized around splicing factors (such as the serine/arginine rich (SR) proteins that process transcribed RNA) and scaffolding proteins (such as the Runt-related transcription factors, Runx) at specific sites of target-gene promoters to facilitate co-regulator recruitment. These micro-processing domains are known to harbor protein arginine methyltransferases (PRMTs) and Runx1 transcriptional activity is regulated by arginine methylation mediated by PRMT1. Krainer’s lab at Cold Spring Harbor recently reported on the potentially complex relationships between protein charge, methylation and the intracellular targeting and functions of a prototypical SR splicing protein.
Zaidi et al. describe several gene bookmarking functions in development, lineage commitment and disease. DNA sequence-specific protein associations that exhibit accessibility to single strand nucleases in promoter regions only during mitosis mark target genes for rapid transcription following mitosis. For example, the single strand DNA binding protein, hnRNPK, can modulate transcription from the MYC promoter in this manner. The basis for the preferential association/disassociation of hnRNPK from the DNA is not clear, but perhaps the interaction depends on protein methylation state. Similarly, Runx1 associates with Pol I transcribed ribosomal RNA (rRNA) genes and Pol II phenotype-specific genes involved in growth and differentiation, marking those genes for repression during early G1.
The recruitment of the methylarginine co-activator, CREB-binding protein (CBP), by specific transcription factors to the globin gene locus serves to enforce lineage-restricted expression of globin genes by supporting rapid post-mitotic gene activation. CCAAT/enhancer-binding proteins (C/EBPa, ß, ð) also associate in a phenotype-specific way with mitotic chromosomes to mediate a program of growth and differentiation. What role may be played by the arginine methylation of C/EBP ß in lineage commitment and gene bookmarking, perhaps like the methylation of CBP, remains to be determined.
When Gene Bookmarking Goes Bad
Alterations in gene bookmarking may also form the basis for some human diseases. The association of the leukemogenic fusion protein, Runx1-ETO, with mitotic chromosomes up-regulates rRNA synthesis and may act as an epigenetic switch for unregulated cell proliferation. Mixed lineage leukemia (MLL) protein, which is associated with the blood cell cancer, can also occupy mitotic chromatin to promote transcriptional reactivation after mitosis. Interestingly, there is a requirement for catalytically active PRMT1 in a mouse model of MLL-mediated leukemic transformation.
So, work on mitotic bookmarking is expanding our understanding of the increasing range of the epigenetic mechanisms that operate in biological systems. And to the inquisitive observer, protein arginine methylation appears likely to be a significant part of the unfolding evidence. Stay tuned for more.
**Thanks to John Aletta, from CH3 BioSystems for contributing this peice**