This is news about research by Ingrid Grummt and colleagues at the German Cancer Research Center (Heidelberg, Germany) and their progress in discovering how instructions coded in DNA are correctly sequenced (silenced or activated). But first, an analogy:
Way way back in the cave-person era of computing (say 1954), a ‘programmer’ would stand at a bank of toggle switches (the metal ones that flick-click on and off) and following ‘code’ written in binary (zeros and ones) would set banks of switches to input commands to the computer. It was demanding work. One switch in the wrong position and the whole program could be ruined.
Now shift this picture of switches and programming to a living cell. The switches are located in the DNA; they are part of the genes that provide the instructions for creating proteins, the building blocks of life. Of course, not all the switches are ‘on’ all the time, in fact, it’s crucial that during the reproduction and growth of cells that the order in which genes are turned on or off follow an appropriate ‘program.’ The program, for example, might be one that guides a cell into becoming a neuron, a nerve cell. So here’s the question: What does the programming? How are the appropriate genes turned on or off in the correct sequence?
Switching is a crude analogy, but it outlines one of the biggest mysteries in biology. It has been known for some time that genes pass their instructions to RNA (primarily as messenger RNA or mRNA), which in turn use the instructions to make proteins. How does the RNA pick up the right instructions at the right time?
Part of the answer is that the genes in the DNA are ‘tagged’ (switched) so that some are active and some are silenced. One of the principal mechanisms for tagging has also been known for some time. It’s called methylation. Special enzymes called methyltransferases attach methyl labels (markers with long carbon chains) to specific bases (in this case cytosine and guanine). The methylation blocks, or silences, the entire gene by making it inaccessible to RNA. But how is it that methyltransferase works on the correct genes? That is the core question.
According to the research of Dr. Grummt and her colleagues, this ‘programming’ of the genes is the work of non-coding RNA, RNA that does not participate in coding instructions for proteins. To test this idea, the scientists injected various non-coding RNAs, which they called pRNA, into cells and observed that this pRNA would attach itself to the location of specific gene switches. At this location, the strand of pRNA forms a kind of braid (a triple helix). The shape of this braid is exactly right for methyltransferase to ‘dock’ (attach) to the braid – and thus fix its location on the correct gene. It’s at this point where the gene becomes methylated – silenced.
At any given time 60%-80% of genes are methylated, turned off. The role of non-coding RNA is crucial in this form of gene regulation.
More than half of our genetic material is transcribed into noncoding RNA. This prompts Ingrid Grummt to speculate: “It is very well possible that there are exactly matching noncoding RNA molecules for all genes that are temporarily silenced. This would explain how such a large number of genes can be selectively turned on and off.”
So, noncoding RNA (ncRNA) is the agent for silencing genes. What triggers the specific ncRNA to carry out its role? Not only is that still a mystery, it’s one that molecular biologists know will be among the most difficult to solve. That’s because, in outline, it is the result of a process called epigenetic regulation, an interaction between molecules in the cell that respond chemically to environmental conditions, which in turn trigger chemistry that produces or activates the ncRNA. Biologists are just beginning to explore this vast subject.