Sunday, November 16, 2008

Non-coding RNA and gene expression

Human DNA consists of about 3.4 billion base pairs. A portion of that is actually genes that code for proteins required by human cells – roughly 20,500 genes. (See here.)

However, it's been recognized for a long time that only about 1.5% of human DNA (in terms of base pairs) actually codes for proteins. Little is known about the purpose (if any) of the remaining 98.5%, even though, by some estimates, 80% of human DNA is transcribed into RNA at some time.

This remainder is often called "junk DNA". But it's also known that a lot of it can't really be "junk", and must serve some useful purpose, because the sequences of large portions of it are highly conserved in evolution, being found almost unchanged in the genomes of human ancestors going back hundreds of millions of years.

Some of the 98.5% really does seem to be without useful function, consisting of stuff like transposons, which are DNA sequences that seem to be copied repeatedly and randomly into various parts of the genome (over evolutionary time spans)

The function of other portions of that 98.5% includes such things as introns found within genes, gene regulatory sequences, and "RNA genes" that code for various kinds of RNA that doesn't wind up being translated into proteins.

Such non-coding RNA can be further classified into things like ribosomal RNA, microRNA, small interfering RNA, and "long non-coding RNA".

This last, known as "long ncRNA" for short, is especially intriguing, because some studies have shown that there may be roughly four times as much of it (in base units) as there is of messenger RNA that is ultimately translated into proteins.

Even though a lot of these long ncRNAs are routinely found floating around inside cells, we're still in the dark about what, if anything, they actually do. But some recent research has revealed a little more about some long ncRNAs:

Early-stage Gene Transcription Creates Access To DNA (10/6/08)
Previously thought to be inert carriers of the genetic instructions from DNA, so-called non-coding RNAs turn out to reveal a novel mechanism for creating access to DNA required by transcriptional activation proteins for successful gene expression, according to Boston College Biology Professor Charles Hoffman, a co-author of the study with researchers from two Japanese universities. ...

Hoffman and his colleagues examined how the yeast cell senses its cellular environment and makes decisions about whether or not to express a gene, in this case fbp1, which encodes an enzyme. What they found was a preliminary transcription phase with a flurry of switches flicked "on" and then "off" as seen by the synthesis of non-coding RNA before the final "on" switch is tripped.

The non-coding RNAs initiate over one thousand base pairs of nucleotides along the DNA away from the known start site for this gene. The group discovered that the process of transcribing non-coding RNAs is required for the eventual production of the protein-encoding RNA. The transient synthesis of these non-coding RNAs serves to unfurl the tightly wound DNA, essentially loosening the structure to allow for gene expression. [Emphasis added.]

And here's the research article, with some of the abstract, providing a somewhat more precise description of what's going on:

Stepwise chromatin remodelling by a cascade of transcription initiation of non-coding RNAs
Here we show that RNA polymerase II (RNAPII) transcription of ncRNAs is required for chromatin remodelling at the fission yeast Schizosaccharomyces pombe fbp1+ locus during transcriptional activation. The chromatin at fbp1+ is progressively converted to an open configuration, as several species of ncRNAs are transcribed through fbp1+. This is coupled with the translocation of RNAPII through the region upstream of the eventual fbp1+ transcriptional start site. Insertion of a transcription terminator into this upstream region abolishes both the cascade of transcription of ncRNAs and the progressive chromatin alteration. Our results demonstrate that transcription through the promoter region is required to make DNA sequences accessible to transcriptional activators and to RNAPII.

To expand on that just a bit, recall that chromatin is the form in which DNA is actually stored for safe keeping. It consists of the double-stranded DNA molecules wrapped around many protein complexes called nucleosomes. Before any stretch of DNA can actually be transcribed into messenger RNA, the DNA has to be unwound from the nucleosomes. The present research has determined that some long ncRNA takes part in this unwinding process.

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