RNA in Scientific American

Well it would seem that in the past couple of years pop science has discovered RNA. Via Genomicron, I found this article in Scientific American from a few years back. Unfortunately all the lit on RNA in the popular press is a little overhyped and not very well understood.

Sure, there is probably a lot of non-coding RNA that does important work. Sure gene regulation through micro-RNAs is one of the biggest discoveries of the last decade. And yes the evolution of eukaryotes is intimately tied in with RNA splicing - the main purpose of the nucleus is to separate mRNA synthesis and processing from mRNA translation. But there is very little data that indicates that the individual introns play important roles after they are spliced out of pre-mRNAs. There is very little data that the bulk of the non-coding RNA plays any importance in development. How many non-coding RNAs have been picked-up in genetic screens? Besides miRNAs, the list is very small. In fact this simple minded reading of the literature by many science journalists is most likely wrong. The most revealing scientific publication that may point out what is happening is not the ENCODE paper, but rather the paper by Marc Buhler from the Moazed lab (see this post). There seems to be an intimate relationship between transcription and DNA packing.

DNA is wrapped up in cells around particles called nucleosomes. Each nucleosome is in turn composed of 8 histone proteins (2 copies of histone 2A, 2B, 3 & 4). There are four things you should know about histones:

1) they are some of the most abundant proteins in the body
2) they are one of the most conserved proteins in eukaryotes
3) they get modified in many, many ways ... these alterations are thought to affect how tightly the nucleosome binds to the DNA
4) there is a certain pattern of nucleosome modifications found along the length of the genome and this pattern can be inherited from mother cell to daughter cells - the transmission of histone modifications is referred to as epigenetics - (cells not only inherit genes but inherit how the genes are packaged)

A big mystery is exactly how could the exact pattern of modification be copied onto a newly synthesized strand of DNA. You may think of the first set of nucleosomes as the "template" but nucleosomes must be stripped off of the DNA in order to separate the two DNA strands which act as templates for each new complimentary strand.

Now there is a second mystery. You see most scientists believe that the pattern of nucleosome modifications and thus the accessability of the underlying DNA dictates whether a certain peice of DNA is transcribed into RNA. But when one finds out that 70% of the genome is transcribed, one is forced to change how we think about nucleosomes, histone modifications and epigenetics.

But in the Buhler paper a funny discovery was made. The Moazed lab looked at parts of the genome that are normally silenced. Part of this silencing was thought to be due to the types of histone modifications found in this part of the genome. But what these guys found was that this DNA was actively transcribed into RNA. A silencing complex (termed the RITS complex) using small siRNAs, can recognize transcripts eminating from these genomic regions and 1) target the transcripts for destruction and 2) enhance histone modification. But surprizingly the histone modifications were needed to promote transcript degredation. So what does this mean? Histone modifications may infact be regulating RNA stability. This turns all of what we know about transcriptional regulation on its head. Also we may have some indication of how the position of histone modifications can be monitored - via transcribed RNA that is associated with complexes such as RITS.

Now everything I described to you was found in ... fission yeast. This has nothing to do with "higher complexity". These findings indicate that gene regulation in eukaryotes is fundamentally different from our current models. Eukaryotes and prokaryotes seem to follow different rules. Gene regulation with bacteria them is much tighter; they don't have many introns, they do not contain the splicing machinery, they don't undergo sexual recombination ... and they don't have nucleosomes!

Think about that.

Here is some advice to any science journalist who is interested in RNA, attend our RNA Data clubs, the RNA society meeting and the upcoming Keystone meetings on transcription and translation. I think that you'll see that it is all much more complicated and interesting then you make it out to be.