While the human genome sequence has transformed our understanding of human biology, it isn’t just the sequence of your DNA that matters, but also how you use it! How are some genes activated and others are silenced? How is this controlled? The answer is epigenetics. Epigenetics has been a hot topic for research over the past decade as it has become clear that aberrant epigenetic control contributes to disease (particularly to cancer). Epigenetic alterations are heritable through cell division, and in some instances are able to behave similarly to mutations in terms of their stability. Importantly, unlike genetic mutations, epigenetic modifications are reversible and therefore have the potential to be manipulated therapeutically. It has also become clear in recent years that epigenetic modifications are sensitive to the environment (for example diet), which has sparked a large amount of public debate and research. This course will give an introduction to the fundamentals of epigenetic control. We will examine epigenetic phenomena that are manifestations of epigenetic control in several organisms, with a focus on mammals. We will examine the interplay between epigenetic control and the environment and finally the role of aberrant epigenetic control in disease. All necessary information will be covered in the lectures, and recommended and required readings will be provided. There are no additional required texts for this course. For those interested, additional information can be obtained in the following textbook. Epigenetics. Allis, Jenuwein, Reinberg and Caparros. Cold Spring Harbour Laboratory Press. ISBN-13: 978-0879697242 | Edition: 1
1.4 Chromatin compaction - heterochromatin versus euchromatin
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Do curso por The University of Melbourne
Epigenetic Control of Gene Expression
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Week 1 - Introduction to Epigenetic Control
An introduction to and definition of epigenetic control of gene expression, and its importance in normal development. We will learn what chromatin is, and how its composition and packaging can alter gene expression. We’ll also discuss the best-characterised epigenetic modification, DNA methylation, and how it is not only implicated in regulating gene expression, but also in maintaining genome stability.
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Dr. Marnie BlewittHead, Molecular Medicine Laboratory
Walter and Eliza Hall Institute of Medical Research
In this lecture, we're going to think about how DNA is packaged into higher
orders of chromatin. So, what what have we talked about in the
last lecture was that the DNA is wrapped around the histone optima, and this is
known as the nucleosome. And so here, you'll see on the bottom of
the slide, a different way to see that. So we have the DNA here,
this is wrapped around the histones, and this is a broader view to see the
beads-on-a-string structure which we talked about last time.
This beads-on-a-string structure, though, can also be condense into a higher order
structure called the 30 nanometre of fibre, which is shown here in this central panel
and this is because histone H1 can interact with other histone H1
molecules and this results in this very higher order chromatin
packaging. So you can then see that this particular
solenoidal type of fibre is much more densely packaged down where each of the
blue dots that are found in here are singular nucleosomes.
If on top of this you then add in scaffolding proteins which are shown in
green in this central panel through here, this further condenses the chromosome
down again. So, now we have the 30 nanometre fibre
attached to scaffolding proteins. So this general structure where we have
the 30 nanometer fibre then attached to different scaffolding proteins is
generally how you find the DNA and the histones during interphase, that is when
the cell isn't dividing, but it needs to be
condensed at a fairly high rate.
So if we look then at another movie to be able to see what this looks like in
comparison to the open chromatin that we looked at in the last lecture.
What you can see is that now when we start movie, you'll see that there's less
motion. So there are less of those other yellow
molecules that can be able to enter into
this highly condensed chromatin. And you can see each of the nucleosomes
again have got the blue, and now zoomed in, have got the blue histones with the
purple DNA wrapped around. But the whole structure is much more
densely compacted than it was in the beads-on-a-string sort of structure that
we saw before. There's one final level of packaging on
top of this interphase chromosome. And that's to get it to a metaphase
chromosome. So a chromosome that would be found in a
dividing cell. So here in this panel is kind of how we
imagine chromosomes always look. Because this is how they tend to be
depicted whenever they're drawn in images.
However, this is only what they look like when the cell is dividing.
And that's because all of the chromosomes need to be heavily condensed down as
tight as they can be So that they can be pulled apart into the two daughter cells.
If you had any open chromatin at this point, you can imagine, you've got in a
drawer, if you had in a drawer two balls of string that were open a
little bit, they'd be hard to pull apart from one another.
They need to be tightly wrapped so that you can properly pull them apart, and
each daughter cell can receive one ball of string each.
So, this happens by the addition of additional scaffold proteins, which are
shown in this panel here with these yellow proteins, and this allows for this
final metaphase chromosome to be produced. So the summary then of how this DNA is
packaged is that we start out with the DNA. The DNA is then wrapped around the
histone proteins to make a nucleosome and this forming the beads-in-a-string
structure. The beads-in-a-string via histone H1
interaction can then have the interaction in the 30 nanometre fibre.
If you add scaffolding proteins on top of this 30 nanometre fibre we then have a an
interface chromosome and finally if it needs to be compacted down more again for
example at metaphase, then we add add a final layer of
scaffolding proteins, that are shown here in yellow, to make what we often think of
as the chromosome, and how we think of it as that X-shaped chromosome.
So now, in this lecture, we're going to think about open chromatin, like the
beads-in-the-string that is shown on the right, versus closed chromatin.
And these various different forms that are shown on the left.
So we have different names for open chromatin and closed chromatin.
And these names came about because of when DNA was first being looked at in the
nucleus and when they were staining with particular dyes.
So open chromatin is generally known as Euchromatin because it was pale in its
stain. So it wasn't densely stained.
It was pale in its staining. And because it was fairly open, there
was, there were less molecules to absorb the DNA stain.
In comparison, heterochromatin is closed chromatin.
And this is because it's densely staining.
And so that's what the term, heterochromatin really means,
where it stems from originally. While Euchromatin or open chromatin,
where you would tend to find active genes, just comes in the one flavour, just
Euchromatin. Heterochromatin comes in a couple of
flavours. Both Facultative Heterochromatin and
Constitutive Heterochromatin. So we are going to go through and explain
what each of these mean. So Facultative Heterochromatin, as its
name implies, suggests that it can differ by cell type.
We've been talking about how tissue specific things can be expressed in one
cell type and not another, so when these genes are epigenetically inactivated and
densely packed down into heterochromatin. Say for example, the haemoglobin gene
might be densely packed down in a neuron, but open in a red blood cell precursor.
Then these genes would be called facultative heterochromatin.
This also, the second example which we will deal with in later lectures which is
the inactive X chromosome which I mentioned is this epigenetic silencing of
one of the two X chromosomes in females. By contrast, then, we have constitutive
heterochromatin. So again, according to its name, it
suggests that the constitutive of heterochromatin is the same in every cell
that you look at. It's unchanging, and that's in because
constitutive heterochromatin performs a structural role.
So you remember that I mentioned that there are epigenetic marks that are
found at the beginnings or the ends of the chromosomes and even at the centre,
called the centromere. So they found, constitutive heterochromatin is
found at the telomeres, there are the ends of the chromosomes.
At the centromeres, which are the centre of the chromosomes, but also in portions
of the sex chromosomes and in this case it tends to be mostly the Y chromosome
but also can be parts of the X chromosome.
So in the next slide here, we can see an image, of chromosomes.
These six different panels, are chromosomes from different species.
And they're staining the dense, constitutive heterochromatin.
These are metaphase chromosomes so they're those that are found in a
dividing cell, and that is why they do in fact look like there's little X’s.
that we imagine chromosomes look like.
In Part A and Part B, so these two panels up here,
you can see this dense, blacker part of the chromosomes are actually marking the
centromeres. So they're marking the centre.
And a great example is just this one here.
The centre of the chromosome. In parts c and d,
so here and here, what you can see is that the ends of the chromosomes
particularly in this right hand panel, the ends of the chromosome,
say for example, if you would look at that chromosome are more darkly and more
densely staining and this is constitutive heterochromatin shown at the telomeres.
You can also see on this particular one here
there's also a densely stained end. So, there can be particular autosomes.
So, non-sex chromosomes that also have very densely stained heterochromatin.
And again, this can be seen here. For example, this whole chromosome arm,
this whole upper arm of this chromosome is more densely staining than the lower
arm. And finally in e and f we see that the
sex chromosomes are densely stained. So here in panel f, you can see the X and
Y chromosomes are densely stained and there's only half an X chromosome that is
not. And here in panel e, you can see most of
the Y chromosome is densely stained. And this is actually true throughout most
mammals. The Y chromosome is generally
constitutive heterochromatin and only a couple of genes like the testis-determining
gene are really expressed. So heterochromatin then has a couple of
functions that we've mentioned earlier and we'll talk about again.
The first is for gene silencing and this tends to be more for facultative
heterochromatin. And the second is to help maintain the structural integrity of the
genome. And to help to mock the ends of the
chromosomes in the centre of the chromosomes.
And this tends to be constitutive heterochromatin.
What we know is that each of these different types of chromatin, euchromatin and
heterochromatin have a different set of epigenetic marks.
So there are different punctuation marks if you like that are associated with
each. So here I'll show you a movie that just
summarises these points. That we can see again compare and
contrast between the open open chromatin, the euchromatin and the closed chromatin
or the heterochromatin. So here it's given for the X chromosomes
but the same is true throughout the genome.
So if we watch on the left you'll see the active chromatin, the euchromatin, where
genes are active. And on the right, the inactive
heterochromatin where genes are silenced or off.
And if you look at the movies we'll then see that there are a particular set of
epigenetic marks that are made on each. So there are active histone tail
modifications on those internal tails that protrude out of the nuclear zone in
the active heterochromatin. And a different set of those in the
heterochromatin. So they differently coloured.
In addition, there's DNA methylation found on the heterochromatin.
So it's in the next lectures that we'll go through these histone tail modifications
in addition to the DNA methylation.
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