Don't forget the editor: the fundamental role of RNA editing

The genome is a plastic thing. Yes, that's right: the genome is plastic. No, it's not true that an individual's DNA doesn't change. It's not true that genes dictate what we are, and it's not true that DNA is just a set of instructions. And that we can "build" an organism by simply giving a string of As, Gs, Ts, and Cs.

No.

There's so much more to genomes than nucleotides and genes. If you've been following me from my very first post back in July, I hope the message has come through now. Epigenetic changes can alter the way genes are expressed, and some of these changes are passed to the following generations. RNA can act as a gene "silencer," "turning genes off" as a response to a numerous number of environmental stimuli. Jumping genes can move around the genome, increase its size, cause insertions and deletions, and most of these changes are somatic, in other words, they are not "coded" in the DNA. Genes interact together and act as an orchestra rather than push-buttons. Sense and antisense genes can compete for expression. RNA sequences can be altered through RNA editing, which can happen at different levels and result in different protein functionality.

Bottom line: who we are is the result of a very complex and intricate network of different mechanisms inter-playing together. You can't just pluck one out and say, "A-ha! This is it!" as much as you can't play Beethoven without the whole orchestra.

The idea that genes were the equivalent of proteins (I don't mean literally, but conceptually equivalent, in the sense that proteins are viewed as the direct product of genes) has prevailed for many years, until we learned the true importance of RNA. Its role goes beyond that of a mere intermediate between DNA and proteins, and new studies have brought to life a new aspect of RNA, which is that of regulatory agent. Bits of microRNA can bind to their complementary strands, effectively silencing a gene. Or, it can be modified through enzymes and change the functionality of the proteins it codes -- a mechanism called RNA editing. All together these processes confer a plasticity to the way RNA, DNA and proteins interact together which allows adaptation to the environment, and it's especially active in the brain.

As John Mattick explains in [1],

"The ability to edit RNA, much of which occurs in noncoding sequences, suggests that not only proteins but also – and perhaps more importantly – regulatory sequences can be modulated in response to external signals and that this information may feedback via RNA-directed chromatin modifications into epigenetic memory."

Genes interact with the environment at two levels: short-term responses can alter gene expression; but also more stable phenotypic changes can occur in reaction to environmental stimuli, which affect underlying epigenetic processes.

"RNA sequences can also be altered by RNA editing, which suggests an evolved ability to overwrite hard-wired genetic information, thereby providing the molecular basis for plasticity in the system."

Interestingly, one of the ways RNA gets edited is through the use of APOBEC, a family of enzymes the existence of which I learned from HIV. Every now and then you come across a sample of HIV sequences (from a single patient and single point in time) where you see an extensive number of G to A mutations. That is how the APOBEC3G enzyme re-edits the viral HIV and by doing so it can impair the virus life cycle [2]. Little I knew, APOBEC enzymes edit human RNA too. Mattick lists numerous examples where the activity of the APOBEC enzymes has been found, and even though he notices their importance as defenses against retroviral infections (as in the case of HIV), he also formulates an interesting hypothesis:

"An alternative and exciting possibility is that these enzymes have evolved and expanded not (simply) to defend against the movement and activity of endogenous retroviruses (ERVs) and retrotransposons, but to regulate evolved functions associated with the domestication of such sequences as agents of epigenetic regulation and somatic plasticity, especially in mammals and primates."

Basically, what Mattick is saying is that rather than just "destroying" the viral sequences, these enzymes may have played a role in integrating them in our DNA and "reusing" them, as for example in the case of endogenous viral sequences expressed in the placenta.

The more I read about these things the more I realize how much I don't know. The genome keeps surprising me with its amazing plasticity and adaptability. DNA is far more than a code. It's life, and there's no life without complexity and change.

[1] Mattick JS (2010). RNA as the substrate for epigenome-environment interactions: RNA guidance of epigenetic processes and the expansion of RNA editing in animals underpins development, phenotypic plasticity, learning, and cognition. BioEssays : news and reviews in molecular, cellular and developmental biology, 32 (7), 548-52 PMID: 20544741

[2] Chiu, Y., Soros, V., Kreisberg, J., Stopak, K., Yonemoto, W., & Greene, W. (2005). Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells Nature, 435 (7038), 108-114 DOI: 10.1038/nature03493