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
1.2 Mitotic heritability of epigenetic marks
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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
So, epigenetic control isn't just important in the differentiation of the
three cell types we spoke about in the last lecture, but in fact, it's important
throughout development. And this is consistent with the idea that
I mentioned that epigenetic marks demarcate the beginnings and the ends of
chromosomes and the middle of chromosomes. So, because epigenetic control is
important in chromosome structure, as well as in the control of gene
expression, of course, that's important for every cell type.
So, here I'm showing you in this diagram that epigenetic control is important
throughout development, from the single cell fertilised egg, or otherwise known as
the zygote. Through pre-implantation development.
So, this is before the embryo has actually implanted into the uterus to
make a placenta. Post implantation development, this
strange looking embryo here, through mid gestation development.
The development of many different cell types in the adult.
For example here, showing the blood cell system.
and even through to the generation of the sperm and the eggs.
Particular epigenetic marks are very important in this case, because these
highly specialised structures, the sperm and the egg require a unique set of
epigenetic marks to be able to allow their particular functions.
So, these epigenetic marks are laid down throughout development and this
helps to ensure, to specify cellular identity, and for that cellular identity
to be maintained. But in addition, these marks need to be
removed between development. And that's why there's this break in the
arrow here, to indicate that they're removed between generations to ensure
totipotency for the next generation. So, as you might expect then for this
ubiquitously important process of epigenetic control.
When it goes wrong, it results in a wide array of different disorders and
some of these we'll cover in later lectures.
For example, the imprinting disorders, and these result of epigenetic control
goes wrong in either the gametes or in early development.
Abhorrent epigenetic control can result in early embryonic lethality, slightly later
early embryonic lethality if the placenta fails, and it can result in many
different types of tumours. So for example, germ cell tumours, so
these are the ones for example, found in the ovary, where an oocyte will generate a
tumour. And because of its ability to be able to
make many different cell types when fertilised by a sperm, a tumour derived from these
cells can actually have many different cell types in there as well.
And tumour genesis in the adult of many different kinds, so for example leukaemia is
found in the blood system, skin cancer, breast cancer, colon cancer, any cancer
that you can think of has epigenetic abnormalities.
And we're going to spend some time thinking about this in later lectures.
Abhorrent epigenetic control or epigenetic mistakes are also found and
result in blocks of differentiation. What I mean here is that, a cell that is
a precursor cell for example, of a B cell may not be able to actually make a mature
B cell, cannot continue to progress through to make a mature B cell
And instead, gets stuck at a earlier
stage, if there are some epigenetic abnormalities.
And finally, if you don't have appropriate epigenetic control in the egg
and the sperm, this results in infertility.
So, in each of these cases we're talking about, throughout development, we're
talking about cells that have identical genetic information and yet they have
different cellular makeups. But if you think about it we also know
this doesn't just happen with genetically identical cells within one person but we
know that there are examples of genetically identical people.
So that is identical twins, monozygotic twins.
What's interesting about monozygotic twins is sometimes they actually display,
they look a little different so they're a bit discordant for their phenotype or
their phenotypic makeup but on some occasions they're even discordant for
disease. So this is really the same situation but
instead of being a cell by cell basis now, it's instead the difference between
individuals. So just to remind you, the way that
identical twins are made. It's you have a single egg and a single
sperm undergo fertilisation. This embryo, zygote, this single cell
fertilised egg here will then divide to make a two cell embryo.
And at the two-cell stage or later, it splits to make two separate embryos.
But because they derived from the same sperm and the same egg, they are
absolutely genetically identical. So what's interesting in this light is
that identical twins can sometimes have different appearances.
So these two twin little boys that you're seeing here don't really have different
appearances. They look very similar.
But we actually know if you take any particular phenotypic trait, and you
measure it, say for example, height, which is obviously a nice quantitative
trait, then about 30% of twin pairs will be different in their measure of height.
The same is true if you look at almost any other trait that you can measure and
indeed, it's also true for disease. So sometimes you'll find that there'll be
a twin pair that both carry a disease gene but only one of them is afflicted.
So this is a very interesting scenario. And, and what we really want to ask is,
well, why can this occur, and how does it occur.
Because if we can work out how it happens in the first place perhaps
we can learn how to treat the disorder. Perhaps we can work out why one of those
twins is is healthy despite them carrying that disease gene.
So what's become clear in the recent years is that perhaps this is
because sometimes these genetically identical twins are epigenetically
different. And again this is something we'll deal
with in the later slides. So it's now time to think about how we
can define epigenetics. I told you about when it was first used
and it was used with this prefix ‘epi’ just to be able to say that there was
additional information in addition to the genetic information.
So, Conrad Waddington was one of the first people to use this term back in the
1940s. And he said that the study of epigenesis
was really thinking about how the genotypes can give rise to the phenotypes
during development. And this is what we've already mentioned,
essentially. In 1990, Robin Holiday updated this
definition. And he took into account what we started
to know in basically 50 years of science,
and said that as epigenetics is really the temporal and spacial control of gene
activity during the development of an organism.
The definition that we will use for this course, and it's commonly used
in the epigenetics field has a little bit more molecular detail to it.
And so our current definition is really based on that of Art Riggs.
And it said that epigenetics is the study of mitotically heritable, and this is
important, mitotically heritable changes in gene expression that occur without
changes in DNA sequence, and this is also very important.
So we're not talking about changes in single nuclear type polymorphisms,
for example, that exist between people. But rather we're talking about changes
that don't require those genetic changes. They occur without genetic changes, with
no change in the DNA sequence. The mitotic heritability is important,
and we're going to deal with this in the coming slides.
but this is something that's quite controversial in the field of
epigenetics. There are those that say that this is not
actually required for an epigenetic mark, although I think the majority of the
field would say that it is. So, we'll stick with the definition in
this course that it's in general required for mitotic heritability.
But I will introduce a couple of examples, and explain about those
that aren't necessarily mitotically heritable.
So lets think about this mitotic heritability and what it really means.
Well if you take the single cell here and when it divides if it copies over all of
the epigenetic marks that it has to its two daughter cells then those epigenetic
marks will bring about the same changes in gene expression or the same gene
expression profiles and so the two daughter cells will have the same
phenotype, the same function as the parent cell, and so on for the next
generation. So, this epigenetic heritability, the
mitotic heritability means that the same sets of genes will be expressed in the
daughter cells, as I just said, but also ensures tissue homogeneity.
So if you think of a liver cell, when it devides, it should produce more liver
cells so that we have a liver that is homogenous and is always made up of liver
cells and nothing else. If you take away the mitotic
heritability, this aspect of epigenetic control, then when we have this same
liver cell what happens now is that the resulting progeny cells will have a
different set of epigenetic marks, and therefore, a different
phenotypic outcome, a different function and this will result in different cell
types. So here, you know, this green cell and
the purple cell, and the result of them could result in, again, a wide variety of
phenotypes, in the particular cell and therefore functions.
So, this would mean that you would have tissue heterogeneity, a wide variety of
different cell types all found in the one location. And we know that this isn't
usually the case. So it's mitotic heritability that will
allow cellular identity to be to be maintained.
So as I mentioned earlier, this heritability and this mitotic
heritability throughout development is also counted by particular periods when
epigenetic marks are removed. So, I mentioned earlier that this happens
and this is shown here by this break in the slide, that it happens in the germ
cells and also it happens for a second time in early development.
If you think about why this might need to happen I think it makes quite good sense.
The somatic cells from which an egg or a sperm are derived are really nothing like
an egg or a sperm. And so we need to remove the epigenetic
marks that are found in each of those cases and lay down a fresh set of marks,
that are unique to the egg or the sperm to allow the expression of the genes
required for each of these cell types. Similarly, once this egg and sperm have
gone on to form the zygote, then we need to remove the epigenetic marks that were
found in the egg and the sperm that were specific to those particular features.
And now lay down those that are required to make a totipotent cell mass that
can perform all of the cells or all of the different types of tissues in the
adult organism. So, these are the two, what’s generally
considered as epigenetic reprogramming, which we'll go into more detail in the
later slides, but epigenetic reprogramming or remodelling and removal
of epigenetic marks also happens at particular other time points within
differentiation. And these ones are perhaps less well understood or studied
at the moment but we certainly know still occur.
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