So the question now becomes what are these long noncoding RNAs doing?
And are the ones that are found at such low copy really doing anything, or are
they perhaps just the result of transcriptional read-through, or
transcriptional noise in the genome. What's interesting about the ones that
have been characterised is that these long noncoding RNAs appear to regulate
epigenetic processes. And this is what's interesting for them
in relation to epigenetic control in this course.
So these long noncoding RNAs can regulate many different processes. And as I said,
there are a very large number of them. But there's a smaller set of them that
have been characterised in any detail. We're going to talk about Xist as well
as HOTAIR, and these two long noncoding RNAs have roles in X inactivation for
Xist and Hox gene silencing for HOTAIR. You'll recall X inactivation, the dosage
compensation mechanism in female mammals. It actually involves a very large number
of long noncoding RNAs. But, the prime example is Xist.
And this was indeed, the first long noncoding RNA to be discovered back in
1991. There are many more that have been
discovered since that have a role in X inactivation, including Tsix.
Genomic imprinting, which I introduced in the last lecture just with a couple of
sentences, this mono allelic expression of genes between that differs, or is based
on, the parent of origin of the gene. Also can involve long noncoding RNAs that have
been very well studied. And Hox gene silencing involved HOTAIR
which we'll talk about. This long noncoding RNA called HOTAIR.
So, Hox gene silencing we have a large number of Hox genes in our genome and these
are involved in setting up the segmentation through the body axis.
So, for example if you think of your vertebrae.
So each Hox gene needs to be on at a particular region, and then is switched
off in other regions. And this switching off involves this long
noncoding RNA called HOTAIR. Finally there are other, many other
processes that are regulated in, with long noncoding RNAs including DNA damage
response. So, what do these long noncoding RNAs
actually do? Well, you'll remember one of these
longstanding questions in the field of epigenetics that I brought up in the
previous lecture was, how are the epigenetic complexes
so, the complexes, the laying down of DNA methylation or histone modifications, or
that are moving around the nucleosomes, the chromatin remodellers, how are these
actually targeted to specific sites in the DNA?
We know that most sites actually don't have much DNA binding specificity.
so your most complexes don't have the DNA binding specificity all of their own.
So we also know there are transcription factors, these factors that that would
bind with RNA polymerase. And they can provide some sequence
specificity. However, the sequence specificity that's
provided by a transcription factor is, tends to not be, particularly high.
So they may recognise maybe a 6 base recognition sequence or even a 12 base
recognition sequence. But if you calculate the number of times
that these 6 or 12 base recognition sequences can be found in the mammalian
genome. It doesn't allow for unique targeting of
any complex but rather there'll be thousands of these sites spread
throughout the genome. So finally we also said that we can, the
chromatin remodelling complexes, for example, will be targeted based on
previous histone marks or histone, they will bind to histone, other histone
marks. And we know also there are some
epigenetic complexes that lay down a histone modification that also bind a
previously made histone modification. But again this doesn't allow for that
specificity. We don't get to come down to just a few
loci, or one allele in by using just these mechanisms.
So, the features of long noncoding RNAs somehow allow them to direct these
epigenetic complexes, at least in some instances that we know about at the
moment. And they appear able to do this in cis,
so in other words. On the chromosome from which they are
transcribed. Or in trans, so acting somewhere else.
They do this amongst other functions. There are many functions that we'll come
to, and we're just going to go through these ones that are concentrating on them
directing the epigenetic machinery. So, what are the features that allow them
to be involved in this targeting, and especially to allow this
allele-specificity? Well, because they are transcribed.
While they are being transcribed from a particular locus from a particular
chromosome they are still tethered there. They're still tethered to the place from
which they're being transcribed. So this allows for that allele
specificity. And it also shows how they might act in cis.
Now the reason they can have provide specificity that's greater than that
of a transcription factor is simply because of their length. Because of the
length of the molecule, the length being over 200 nucleotides in
length and in fact most long noncoding RNA is about which we know something at
the moment a several kilo-bases or tens of kilo-bases in length.
So this means thousands of bases, of course.
This really gives unparalleled site-specificity to these long noncoding
RNAs. But it's important to note that this
specificity and to the allele or specificity based on the
sequence is not necessarily always required for their function.