Dr. Wolf Reik discusses the challenges in DNA methylation sequencing and the next big swings in epigenetic modification sequencing and discovery. This interview took place at the Keystone Symposia’s Epigenomics and Chromatin Dynamics joint meeting in January, 2012.
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Sequencing DNA Methylation Past, Present, Future
Clearly the technology of being able to sequence these new modifications is evolving fast. So right now we have this problem that bisulfide sequencing, which for a long time was kind of wonderful, beautiful, gold standard method of choice to sequence DNA methylation in the genome, now we know it can’t distinguish between methyl and hydroxymethyl. So I think one big challenge out there is to develop…of course there are other methods, antibody based, chemical pull-down based, which can sequence these modifications, but not at this point at single-base resolution, single nucleotide resolution. And so I think that’s one of the big challenges out there, to develop methods which can detect all of these modifications basically at single nucleotide resolution.
We have a very enjoyable collaboration with a chemist in Cambridge actually, Shankar Balasubramanian, who is actually the co-discoverer of the Solexa Illumina technology and he’s the inventor of the actual Illumina technology that we’re all using with great effect out there and we have a very, very enjoyable collaboration to look at how we can detect and sequence and how we can make the detection methods better and better resolution, et cetera, et cetera. So I think that’s part of the new momentum that’s developing in the field; it’s really important.
“…I think these third generation sequencing technologies have the potential indeed to unveil potentially new DNA modifications that we don’t know.”
Now the other things that’s on the horizon in this respect are the third generation sequencing machines, so there is already the potential that PacBio machines for example have already shown altered potentially…Oxford Nanopore machines have shown by single molecule DNA sequencing you could potentially detect the modifications on single molecules of DNA in third generation type sequencing. So I think that will be a very important horizon the future as well.
I think if those technologies work out and show more promise and additional promise in the future, then you can imagine that you can put any piece of DNA into those machines and you can get all sorts of new, exciting read-outs, which you don’t know what they are initially. You may not be able to associate them with the known DNA modifications. It’s a little bit like putting elementary particles into the large Hadron Collider in Geneva. Any kind of things may pop out, new things may pop out and I think these third generation sequencing technologies have the potential indeed to unveil potentially new DNA modifications that we don’t know. Those may be repair associated or damage associated DNA modifications. They may be reprogramming associated DNA modifications. They may be new epigenetic signals. So this not only stops at DNA, this also ties to RNA for example. There’s a whole world out there of RNA modifications that remain to be discovered I think.