2.4 Histone variants

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Epigenetic Control of Gene Expression

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The University of Melbourne

Epigenetic Control of Gene Expression

398 ratings

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

From the lesson

Week 2 - Epigenetic Modifications and Organisation of the Nucleus

We’ll discuss the molecular mechanisms for regulating gene expression in some detail, from how the DNA is packaged at a local level, right up to how the chromatin is positioned within the nucleus. We’ll learn about the chromatin modifications implicated in gene silencing and activation, the role of non-coding RNA, and higher order chromatin structures. This week will provide you with a good understanding of the basic mechanisms that will help you understand the processes we discuss throughout the rest of the course.

2.1 Introduction to histone tail modifications4:13

2.2 Histone acetylation and histone methylation12:38

2.3 Chromatin remodelling12:58

2.4 Histone variants8:30

2.5 Noncoding RNAs - microRNAs6:48

2.6 Noncoding RNAs - piRNAs9:18

2.7 Noncoding RNAs - long noncoding RNAs introduction10:32

2.8 Long noncoding RNAs Xist and HOTAIR7:45

2.9 3D organisation of the nucleus and summary of epigenetic marks17:27

Meet the Instructors

Dr. Marnie Blewitt
Head, Molecular Medicine Laboratory
Walter and Eliza Hall Institute of Medical Research

So the next thing we're going to talk about are histone variants.

So histone variants are different forms of the canonical histones that

normally make up the nucleosome, so rather than being one of the regular

histones, they have some difference about them, which allows a different function.

So there are known to be different variants for histone H2A, H3, and H1.

And today I'm going to take you through three examples, and these are

going to be only of histone H2A and H3. So there are very many variants that

can be found in for histones. And each of these have different

properties, which will allow them to change something about their nucleosome

For example, they might allow increased

stability of the nucleosome or decreased stability.

They might have particular amino acids that can be modified in a different way

that the normal core histones don't have. Or they may have some other functionality

that we don't yet understand. So, you'll remember in the last lecture

that I mentioned that histone variants need to be deposited and this involves

the chromatin remodellers. The ATP-dependent chromatin remodelling

proteins. So importantly, the histone variant

deposition can happen at the time of replication, so it can be dependent on

replication, or it can be replication independent.

In other words, the cell wouldn't have to divide for this happen for a nucleosome to be

changed and the histone variant to be included.

And this is important depending on the type of nucleosome or the type of histone

variant and its function. We wouldn't always want to have to wait

until the cell divides to be able to incorporate these variants.

So we'll now go through those three examples I said we'd go through.

The first of which is a variant in histone H3, and this called CENP-A.

This centromeric histone variant, and you find some form of CENP-A in basically all

organisms, because all organisms with chromosomes need to have a centromere.

The function of the centromere as it's shown here down in this metaphase

chromosome that's pictured is it's the central constriction of the chromosome.

And it is where these chromosomes during division attach to the mitotic spindle.

And it's the mitotic spindle, that, when a nucleus is actually dividing the

chromosomes. That, when the chromosomes are attached,

it pulls them to the opposite poles of the cell.

So it's very important to have a centromere to ensure that when

replication, happens, and division happens, you get one copy of each

chromosome to each daughter cell. So it's very important for genomic

stability in that way. What's interesting about CENP-A is that,

it binds through this region here at the centromere.

And this is the same region where we have a lot of repetitive DNA.

And it's been thought for a long time that it's the repetitive DNA which

defines the centromere. However it's relatively recently been

shown that this isn't the case. You can form a centromere somewhere else.

If for example, you have a truncation which gets rid of the portion of the

chromosome that would normally contain the centromere, the remaining part

sometimes will be able to form a neo- centromere, and this neo-centromere does

not form necessarily where there's repetitive DNA but rather is simply

defined by the CENP-A protein. This particular histone variant

which changes the nucleosomes in that region.

In this way, CENP-A really has some kind of a structural role.

It does change the packaging of the DNA in the region, but it's having a

structural role in maintaining genomic stability.

The second Histone variant we want to think about is called H2A.X, so its a

variant of Histone H2A. And this variant is involved in DNA

repair. So it's a universal histone variant,

somewhat like CENP-A. It's found in all organisms, and it's

very highly conserved. And in this case, it's the C terminal

motif that differs from the normal histone H3 that's found in regular

nucleosomes. And this particular C terminal motif

contains a serine at residue 139. And serine is an amino acid that can be

phosphorylated. And it's the phosphorylated form of

H2A.X, which we, we call gamma H2A.X, which is found in double strand breaks.

So, double strand breaks can happen through a variety of insults

to the cell. And, but of course, these double strand

breaks need to be repaired. And so by having this gamma-H2A.X that marks

those double-strand breaks, this enables repair to happen at the right places.

So, the serine 139 is phosphorylated by kinases, and this makes the gamma-H2A.X,

and this happens at the double-strand breaks.

And then it is this gamma H2A.X which is then able to recruit DNA repair proteins.

So it's not only DNA repair proteins that are recruited by gamma H2AX, but also

epigenetic factors. And this is quite interesting, because,

to be able to repair the DNA, just like to be able to transcribe it or to

replicate it, you need to have accessibility to each individual base

within the region. And so, the chromatin needs to be

unwound in the region that needs to be repaired.

It will be repaired and then wound back up again.

So DNA repair is an intimate association between the repair machinery and the

epigenetic machinery. Once this repair is complete, then we

have a phosphotase that comes along and cleaves the phosphate group.

So if you have, this image here is a nucleus which, where the DNA is stained

by DAPI, and this is a blue dye. But the gamma H2A.X is stained with green.

And so you can see these densely green phosi spread throughout the nucleus

and these are all where the double strand breaks are clustering.

This a nucleus that's been exposed through a radiation and this is what we

can say gamma H2A.X at all within the nucleus.

You remember that I mentioned that these, the histone variants can be incorporated

into nucleosomes, either in a replication dependent manner or

replication independent manner. And this one of those cases where

it's really important that it is a replication-independent manner.

We certainly wouldn't want the cell to have to divide, a cell that has DNA

damage to divide, in order to incorporate gamma H2A.X, in order to be able to then

repair the DNA. You certainly, that's exactly when you

want to stop, when a cell has DNA damage. So this is an instance where gamma H2A.X

can be incorporated before DNA replication takes place.

The 3rd example is another variant of histone H2A called macroH2A.

So, as you might expect this, histone variant has a macro domain.

And the macro domain is just inferring that it has a very large, domain.

In this case, 200 amino acids at its C terminus.

And we don't yet understand the function of this macro domain.

What we do know is that, unlike the previous two histone variants I

mentioned, this macroH2A is only found in vertebrates. And that's

particularly interesting because what we know it's involved in is X inactivation.

It seems to be associated quite densely with the inactive X chromosome.

X inactivation only happens in precisely the same way in mammals.

So perhaps, then it wouldn't be surprising that macroH2A would only be

can only be found in higher organisms, only found in vertebrates.

So, you'll also remember that the inactive X chromosome, it's made up of

facultative heterochromatin. That is, that it's not the same in every

cell type. It can vary, because it could be either

the paternal or the maternal X chromosome that is silenced. And that can vary by

cells, with each cell. So it's possible that macroH2A is found

in other forms of facultative heterochromatin as well.

So to summarise what we've said about histone variants, we know there are many

different variants, and we've just covered 3 in very brief detail.

These variance, the cool thing about these variances that have particular

domains or particular residues or some difference to the core histones, the

canonical histones, and it's these differences that allow particular

functionalities. So we know that key histone variants can be

involved in many different things. They can be involved in structural

aspects. In other words like CENP-A, which is

involved which is involved in making centromeres.

They can be involved in DNA repair, such as H2A.X, which can be phosphorylated and

called gamma-H2A.X. Or they can be involved in

transcriptional silencing like macroH2A. There are also other histone variants

that can be involved in transcriptional activation.

And, so, in these ways histone variants contribute to epigenetic control.

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