How chromosomes get their X shape - Interview with Professor Daniel Panne

Professor Daniel Panne discusses his work looking at the structure of chromosomes.

Episode Transcript

(00:00):
I'm Turi King, professor of public engagement at the University of Leicester and today
I'm talking to Daniel Panne, who is professor in structural biology in the
department of molecular and cell biology.We're going to be talking about Daniel's
recent research which has garnered worldwide attention in a little bit, but Daniel for those
who don't know what is structural biology?So structural biology is a discipline that

(00:26):
aims to understand biological function at the level of atoms. Once you understand
the biology at atomic level then you can dissect it, you can probe it in a much more
detailed way that you couldn't do before.So, the first step is try to understand
how things work, you know, underlying many reactions are tiny molecular machines and

(00:49):
if they break then things can go wrong, and so to understand that it's important
to visualise it really at a high resolution.I was going to say how do you examine that?
We use a technique called cryo-electron microscopy or x-ray crystallography,
where we isolate the molecules, and we try to coax them to grow crystals. It's a quite

(01:11):
labour intensive and difficult process and then we go to large international facilities
around the world where we can collect data.So, it's kind of like 3D puzzle pieces isn't
it because if you know what a structure is of a molecule or a protein or whatever,
you can see how the shapes might interact with one another and that might give you
an indication as to what reactions are going on here, why are they joining, that kind of thing.

(01:34):
Yeah, the funny thing is frequently let's say if you have two proteins that
interact and you have a structure of those interacting, that doesn't necessarily tell
you directly what they're doing, but when you then probe the interaction using experiments,
then you can work out exactly what's happening.So, what prompted your interest in this field of

(01:55):
study what got you into structural biology?When I was a student I was always interested
in why something happens, not just what is happening and describing it at superficial level,
but really why, and drilling down understanding it at a detailed level and ultimately if you ask
that, you drill down more and more and you end up at the level of the atoms,

(02:18):
and that's what I thought is the most fascinating.And was there something that you were looking at,
at the time that you were trying to kind of really understand?
Yes, so at the time when I started out, I was looking at how a gene gets regulated. So, this
is a complicated process involving many factors that regulate the expression of a gene, and so

(02:40):
I studied one particular model system in great detail and worked out all the structural details
of how this works, and this is now the best understood system for how a gene gets regulated.
And that's the thing people they hear about genes, they know that they code for proteins sometimes,
but they are expressed and they're things that affect whether or not a gene is kind of,
I suppose turned on or turned off, that's the sort of thing you were looking at.

(03:03):
Exactly so what I worked on is to try to understand how a gene gets turned on, and try
to understand all the players that are involved at the sort of atomic level, how do they do that,
and it's a pretty big deal because imagine you can understand it for one system, then you can
kind of extrapolate and you can say oh it's probably other systems work quite similarly.

(03:24):
So, what's your research these days, what's the sort of, the area of research that you work in now?
So, what we learned in the gene regulation field is that genes are sometimes regulated by segments
of DNA that can be very far away from the gene itself. People know already for a long time
that there must be some kind of long-range three-dimensional contact that's formed,

(03:48):
and so about 10 years ago I started to work on this problem, how do certain protein machines
enable these long-range contacts on DNA.So that's really fascinating
stuff because you're wondering about how the genome is interacting with itself.
Yes, so the genome is folded constantly on itself and that's a reaction that's

(04:14):
being used to regulate, actually we think many aspects are how the genome works.
So I know that three years ago you came out with quite a big paper and you were looking
at this genome folding, so for those of us who don't know what is, talk us through it,
so the genome it comes with these chromosomes, they're really long molecules, so meters long,

(04:37):
that have to be sort of packaged up into our cells and you were looking
at chromosome folding, so tell us about that.Yes, so the genome in our cells is about two
meters long. So it gets packaged into smaller units and then these units get folded into three
dimensions, and we got interested in certain protein machines that do this folding reaction,

(05:02):
how do these machines operate, how they're regulated, and so a couple of years ago we
realised that there's certain interactions are formed of this machine that we're looking at,
and we realise that this is really key for how the genome gets folded.
So, what's useful about knowing about how the genome is folded correctly,

(05:25):
what's useful to know about that?It is useful because we think that
gene regulation requires this folding reaction to bring segments of the genome together, when
genes get activated for example. And so, this is a completely new way how to look
at the genome by understanding not only, sort of, what happens in one dimension but also what

(05:47):
happens in three dimensions, and this seems to be a completely new and important aspect of how the
genome works that is completely underexplored.Once you start to understand these interactions
of how one protein it acts with another protein, and you understand the underlying chemistry of
how this works, you can then start to interfere with that, you can for example try to design drugs

(06:13):
that inhibit one particular interaction and only that one and nothing else, in a very specific way.
So that's pretty incredible because you can then start doing sort of precision medicine
to some extent, in terms of you're going to just affect that particular reaction,
how those proteins fit together you're going to interfere with that or understanding how they

(06:36):
do fit together tells you, okay that's normal, this is not normal so what's going
on there. It's all about the shapes, isn’t it?Yes, it's all about the shapes and what's really
exciting in our work is that, once we understand how, you know, these proteins come together and
the exact shape that's required for them to bind to each other, we can then see that in

(06:57):
certain types of disease, in cancer for example, the interaction is perturbed in certain patients,
and then you know, ah here that's the hot spot for maybe how that disease emerges.
And then with that presumably you can start to think about how you can target that and help it to
work better or come up with drugs that might help.Yes, so the motivation for us is initially just

(07:19):
discovery, how does it work, how does these machines operate, but then how does it go wrong,
what does it mean for let's say diagnostics.If you now understand the reaction, you know now,
ah that person has this reaction not working well, there's something wrong there, and so you can
target them with drugs in a very different way.So, you've had a lot of interest in this recent

(07:40):
research that's been looking at the structure of chromosomes, so talk me through what you've
been looking at with that, and what you found, so this is about the X shape of chromosomes. So,
people have been looking at this for over a hundred years, haven't they?
Yes, so you know people in the 19th century, when people looked through the light microscopes for

(08:03):
the first time, and they looked at cells they realised the cells have chromosomes,
and they realise they have certain shapes, and when a cell divides these chromosomes they have
to line up in a certain direction of the cell, and then typically these chromosomes have an X shape,
because they're held together at a certain point, which is very important for how they

(08:25):
then divide it into the two cells that are the progeny or the daughter cells.
So, this actually goes right back to cell division. So our DNA obviously has to be
copied to be passed down to cells, daughter cells, and so the chromosomes which normally kind of look
like worms really don't they, they kind of double up and they're held together in this X shape,

(08:51):
so you've got the two separate chromosomes that are copies of one another, but they're
held together at a particular point and that's really important isn't it for cell division.
It's very central because this point where the chromosomes are held together is required for
the two chromosomes then to come apart into the new daughter cells, and if this doesn't work right

(09:14):
then chromosomes are not evenly distributed, it can lead to trisomies, Down syndrome,
or even cancer.Yeah.
So many cancer tissues have this problem, that these chromosomes are
not properly divided during cell division.So we've got two copies of each of our
chromosomes, so you've got, you know, one chromosome one doubles up and it's
held together in a little X shape, the other chromosome one doubles up it's held together

(09:37):
into a little X shape, and they kind of line up down the centre of the cell don't they,
and then slowly the cell divides from the middle, and what happens is the little X shape starts
to separate and you were looking at how does that happen, kind of like a set of molecular
scissors come along and cut that little bit where they're joined together, that centre of that X,

(09:59):
that's what you were looking at wasn't it?Yeah so, we were studying the machinery that is
important for generating the connection between two chromosomes during this particular state
in cell division. And we realised that a similar reaction we described a couple years ago, is also
happening here with a different protein involved. Quite similar chemistry ultimately when we looked

(10:23):
at it in the structures that we're looking at, but importantly the interaction we looked at when you
change the chemistry slightly then you don't get these X shaped chromosomes any longer. And so,
we now understand at an atomic level what's required for making this X shaped chromosome.
I mean that is huge because it's so important that that little X shape is cut, that they aren't held

(10:46):
together anymore, and then you get one copy goes down each into these two separate cells,
if that little X is not cut you suddenly get too many copies of a particular chromosome goes down
into one of the cells, and the other cell doesn't get its little portion that it should be getting,
that has quite big implications, I mean Down syndrome as you said.

(11:07):
Yes, there are many other diseases where the chromosomes are not evenly segregated,
and so this has really intrigued generations of researchers, how does this work and now
we can sort of put our finger on it.So that's quite a big leap forward
for geneticists and structural biology to finally understand what’s going on there.

(11:29):
What is really fascinating is that when you come from where I come from,
so from the structural biology and the chemistry and you start to realise that,
you know, one chemistry required for holding the X chromosomes together at the attachment point, but
we think that this principle of how this machine is controlled, that we're actually studying here,

(11:51):
is probably not only required for the control of how chromosomes are held together but probably
involved in many aspects of how the genome works.So, once you understand this particular kind of
protein machinery it helps you in terms of understanding other things
that are going on in the cells as well.That's what we think, because we know we
understand this particular reaction we can extrapolate that other important reactions,

(12:13):
for example our genomes need to be repaired, our genomes need to be duplicated,
and many of these fundamental processes will have a three-dimensional component to them,
which is mediated by this reaction we're describing here, we think.
So, what's next for you then?It has opened like a lot of doors for us
because we now can say, okay so this reaction is important for holding sister chromatids together.

(12:40):
Okay now the reaction we described two years ago is important for folding chromosomes in a
completely different state, and now we have many other reactions that we think will use the same
principle. So, we can explore all of these and work out how does folding of the genome
contribute to all genome reactions essentially.Have you got anything that you're particularly

(13:02):
focusing on as your next step then?Yes, we're currently working on the
reaction that involves removal of this machine from chromosomes. If that doesn't work chromosomes
are just held together all along the chromosome arms, and they don't separate at all, and we now

(13:22):
start to understand that process also in quite good detail, and so that's the next step now.
And then we're working on many other aspects of how folding of the genome contributes to,
for example, how the genome gets duplicated, which is also a new frontier for that field.
It sounds amazing, so what really excites you about your work, what is it that gets you

(13:47):
up in the morning and gets you into the lab?So, what's really exciting for me is that we
think we have, sort of, uncovered a new layer of regulation that people haven't really looked at.
People since the early, you know, 19th century and people have wondered how the
genome gets duplicated and it has been studied at very great detail,

(14:10):
but here's a new level of organisation that is completely new and exciting, because we think
we can understand many processes and how folding of the genome contributes to them, because now
for the first time we're starting to understand the players at the molecular level, how do they
work together and all of a sudden new principles of regulation emerge, that is quite exciting,

(14:34):
and so that's what gets me up in the morning.Daniel, it has been such a pleasure to talk to
you, we definitely need to catch up with you as your research projects progress.