Dr. Job Dekker discusses trends that he sees in chromatin structural studies, Chromosome Conformation Capture (3C), and bringing a multidisciplinary approach into the lab to better understand chromosomes. This interview took place at the Keystone Symposia’s Epigenomics and Chromatin Dynamics joint meeting in January, 2012.
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Tackling the Dimensions of Chromatin
I think we’re starting to see generalities in some of these structural features. Of course,
once you have such a large map they raised many new questions as well. And I think
that’s another trend that we now see to be ongoing from just making the genome wide
The second trend I see is going actually back to do single cell studies, mainly using really
improved high resolution imaging so we can much more precisely look at individual load
site and try to combine these two views of the genome. On the one hand, these genome
wide maps, which usually are population based, we’re looking at millions of cells, and
then looking at these same structural features you learned from these maps, but now of
individual cells. And there is sometimes apparently a disconnect between them and
sometimes there’s not.
So there’s an enormous space here, I think, for new studies that I think will more firmly
put the role of 3D structure of chromosomes as a central player in gene regulation. So
these two phenomenons, I think, are really exciting. At this meeting I think we’ve seen
examples already of both of them, if people do exactly these studies, genome wide
interaction mapping and going back to the single cell.
Chromosome Conformation Capture
It is interesting. I started developing Chromosome Conformation Capture, which
became to be known as 3C when I was a post-doc at Harvard in the lab of Nancy
Kleckner. And in that lab we were really interested in trying to understand how
chromosomes can recognize each other. This happens during meiosis, when oocytes
and sperm cells are formed. Homologous chromosomes, they recognize each other. I
was always very fascinated by this problem. How do they recognize each other?
“We’re basically going back to 3C, in which you don’t do any special tricks to scale up the method. You just implant the 3C technology as it was done a decade ago, and just deep sequence everything you find.”
So, at the time I really was interested in taking a biochemical approach to just see can I
cross link two chromosomes and if I do, can I find the points where they recognize each
other. So it had really very little to do at that point of chromosome folding, which we are
currently studying. It was just trying to identify these contact points.
So I spent about four years trying to develop that methodology, which in the end was
very good at finding contact points between and along chromosomes. It was very
successful and we played around with the method for a long time. Other people catched on and
started applying it to specifically look at folding principles, like a formation of a
chromosome loop between a gene over here and a genome and a regulatory element
located far apart. They come together, form a loop, and you can see these things. And it
was all very powerful and people were very excited.
Bringing it Back to 3C
But I think the development of these sequencing methods, like the Illumina platform
and several other deep sequencing methods, really gave this 3C method a big boost,
because now you can start looking at all interactions in the genome. And there has been
this whole range of derived methods from 3C, like 4C and 5C, Hi-C, ChIA PET, and I
think there are some others, a variety of derived names.
But I actually think that this whole field is now going full circle. We’re basically going
back to 3C, in which you don’t do any special tricks to scale up the method. You just
implant the 3C technology as it was done a decade ago, and just deep sequence
everything you find. So sequencing has really – I think without deep sequencing that
these experiments were not possible. We’ve really revolutionized everything.
The Physics of Chromosomes
The chromosomes are actually polymers. These are very long, physical structures and
people in the physics field have studied them for a very long time, not as chromosomes,
but any kind of theoretical polymer.
It turns out chromosomes really behave according to the physics of polymers and the
biology, I think, who acted on these structures, on these basic, physical principles to
fold them. So in order to understand chromosomes, we actually had to understand
polymer physics. For us to understand our 3C data we have to talk to polymer physics to
help us understand it. So, in my lab and in several people I collaborate with, I know
many other people in the field are now setting up these very interesting collaborations
between biologists, computer scientists, physicists, 3D modelers, people from the protein
folding field. They’re all coming together around this topic, so I think it’s a really