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The power and pitfalls of omics part 2: epigenomics, transcriptomics and ME/CFS

Simon McGrath concludes his blog about the remarkable Prof George Davey Smith’s smart ideas for understanding diseases, which may soon be applied to ME/CFS.

George Davey Smith

George Davey Smith

Last November, science star Professor George Davey Smith gave a talk at the UK CFS/ME Research Collaborative (CMRC) Annual Science Conference laying out ideas for bigger, better, smarter research. Although much of his talk wasn’t focused specifically on ME/CFS in particular, his points are of great interest to the ME/CFS community.

This is because Davey Smith has said he’s keen to play a role in the largest research set of studies ever proposed for ME/CFS: Professor Stephen Holgate’s Grand Challenge, which is now moving forward. Davey Smith is one of the most high-powered scientists to ever take on this disease.

Part 1 focused on his remarks about genomics-based research. This final part describes the promises and pitfalls of two other big-data omics approaches that are likely to be applied for the first time on a huge scale to ME/CFS, as part of the Grand Challenge. While genomics examines the DNA itself, these two approaches — epigenomics and transcriptomics — look at how the body makes use of that DNA.

Epigenetics: huge potential, or the confused researcher’s friend?

In his usual sceptical way, Davey Smith started by dousing overenthusiasm about this most fashionable of ’omics. He described epigenetics (epigenomics is just the large-scale study of epigenetics) as ‘the confused researcher’s friend’ — ‘if they ask you anything you don’t know, just say it’s due to epigenetics’.

cartoon

Cartoon from Caroline Renton/OUP blog on epigenetics

He began with a quick primer on epigenetics. Almost every one of an organism’s cells contains essentially the same genetic blueprint, whether it’s a kidney cell, a skin cell, or a brain cell. So some system is needed to tell a kidney cell to run the “kidney cell” portion of the DNA, not the “brain cell” portion.

Epigenetics is the main system that turns some genes on and some genes off long-term, without affecting the DNA sequence itself.

Not only do epigenetic changes affect cells long-term, they are also inherited when cells divide. In some cases, epigenetic changes are passed on to the organism’s offspring. For example, rats exposed to the main psychoactive component of cannabis during adolescence have offspring that are more likely to get addicted to heroin. And epigenetic changes — not changes to the DNA — are responsible for this. It’s less clear as to whether or no human epigenetic changes are passed on.

Image: NIH

The two main types of epigenetic change: DNA methylation (purple diamonds) and histone tail modification (triangles). Graphic: NIH

The most studied type of epigenetic change occurs when cells add a small chemical tag on genes that turns them down, or off. This is called “methylation.” It’s the most stable type of epigenetic change.

(Here’s a recent ME/CFS pilot study on methylation that now has funds for a much larger replication.)

Another way cells do this is by essentially packing some genes away in a closet. Since each minuscule human cell contains about 6 feet of DNA, cells have a system of proteins to wrap that long rope up into a tidy package and then to uncoil it in the spots that are needed.

Altering one of these proteins, known as histones, makes some genes easy to access and use, and some more difficult. That provides another mechanism for epigenetics to affect — which genes get transcribed, and which don’t.

We know that epigenetic changes can perpetuate disease. Take the case of cirrhosis of the liver, a disease typically caused by alcohol abuse or the hepatitis C virus. Yet even if the cause is removed – say, the person stops drinking – the disease continues.

That’s because diseased liver cells have undergone epigenetic changes, and when diseased liver cells divide, said Davey Smith, they produce two sick cells: the new cells don’t revert to being healthy liver cells.

Epigenetic’s role extends beyond switching cells into particular tissue types, and isn’t simply fixed at the cell’s creation, or merely linked. Environmental factors such as smoking can change the epigenetics of a cell after it’s been created.

Researchers have been pursuing this, linking epigenetic changes to environmental factors and to ill health. For example, a media-grabbing study claimed that holocaust survivors’ trauma was passed on to their children by inherited epigenetics. Another story, reported in the Daily Mail, claimed there was an epigenetic test “that reveals if you are gay.”

Most of this is hyped nonsense, Davey Smith said. The holocaust study, for example, was based on a ridiculously small sample of 22 survivors and nine controls. The story about homosexuality was based on just 49 pairs of twins, and the claimed accuracy of 70% isn’t so much better than tossing a coin.

The issues here are very similar to those discussed for genetics in Part 1. Cause and effect are difficult to tease out: are epigenetic changes associated with a disease the cause, or just an effect, of the disease? Furthermore, as with genetic association studies and Mendelian randomization, big sample sizes are essential for robust epigenetic findings.

The forensic epigenome: What our epigenome reveals about us

But epigenetics is important, and not just in making sure we don’t end up as a big blob of identical cells. And Davey Smith has led the way in teasing out solid findings.

A large population study he led showed that smoking by a mother during pregnancy left several clear epigenetic marks on the baby’s DNA at birth — some of which were still present 17 years later. Alcohol drinking as an adult leaves epigenetic fingerprints, too.

Davey Smith said that it was “utterly remarkable” that epigenetics can also accurately predict someone’s age to within a few years which, together with other epigenetic information, can be used to yield valuable information from DNA left at a crime scene. So you might be able to say someone was a 55-year-old heavy drinking ex-smoker, said Davey Smith. “But most 55-year-olds are heavy drinkers who used to smoke, so that may be of limited forensic value”, added the 55-year-old.

A new way to study disease in the lab?

Epigenetic changes could play a role in ME/CFS, and Davey Smith said that there was an intriguing way scientists could determine this — though it’s not yet been done this way (more).

If scientists can identify epigenetic changes that are linked to a disease like ME/CFS, they could potentially use new technology to grow cells in the laboratory with those epigenetic changes, and see if they function differently.

If so, those changes may be driving the disease, and if not, they’re probably just irrelevant passengers along for the ride, as with vitamin E’s link with coronary heart disease. Davey Smith called this possible approach ‘very exciting’.

It relies on use of some very clever technology to turn blood cells into whatever cell types researchers want to study, even neurones. The NIH’s new ME/CFS study plans to use a similar approach to grow and investigate neurones in the lab, starting off with cells from patient blood (though they won’t be looking at epigenetics).

Gene expression (Transcriptomics)

DNA/RNA via Open clipart

While genomics looks at all the DNA, the whole genome, transcriptomics looks at all the RNA. DNA/RNA graphic: openclipart.

To make use of DNA, cells must first copy (or transcribe) bits of it into RNA, a process known as gene expression, or transcription. So another way of studying which pieces of the DNA a cell is using most is to find all the RNA in a cell at a particular moment.

Studying all the RNA produced like this is called ‘transcriptomics’ (as opposed to some gene expression studies that just focus on the RNA transcribed from a limited set of genes).

Yet again, Davey Smith started with scepticism, calling transcriptomics ‘the over-hyped ‘omics before epigenetics came along’. He pointed to the same litany of problems, with studies that were too small and ended up not replicating.

Some work has been done on gene expression in ME/CFS patients. One fascinating small study found distinct gene expression patterns in patients following a moderate exercise test, and those results have apparently been replicated in a larger study, but are yet to be published.

Davey Smith’s warning about size, however, applies to most gene expression studies in ME/CFS so far.

A second problem is that most gene expression studies only use white blood cells — because they are easy to access — rather than the most relevant tissue — such as liver cells — when studying liver disease. Perhaps surprisingly, there is actually some correlation between gene expression in blood cells and that in other tissues, but it’s not a good way to find out what’s going on in the biologically relevant tissues.

A powerful new transcriptomics resource

gtexDavey Smith highlighted a new gene expression research project that has huge potential to overcome these problems, with the opportunity to probe the biological function of any genes that have been associated with disease.

The GTeX project has transcriptomics data for up to 50 different tissues — including the brain — from nearly 1,000 donors, which makes it something of a goldmine. Its ‘secret’ for accessing all tissues is that it measures gene expression in tissues taken from donors who had died only hours earlier (often in traffic accidents).

Crucially, this allows scientists to see how genes are expressed almost everywhere, even in the brain, so researchers can see what happens in tissue that is most relevant to a disease.

One of the great things about the GTeX project is that gene expression data in over 7,000 tissue samples (and growing fast) is ready to be accessed online. For the first time, researchers can search to see what a candidate gene implicated in a disease is actually doing in tissues across the body.

So if researchers identify gene differences that are implicated in ME/CFS, they can now simply dial into GTeX to see affect (if any) those gene differences have in different tissues. They can even look at the effect in the brain, an organ that is often implicated in the illness, but is normally impossible to study.

Two new ways to use omics to probe diseases, including ME/CFS

So Davey Smith highlighted two ingenious news ways to go from simply finding gene or epigenetic differences that are linked to a disease, to exploring their biological relevance.

Potentially, researchers could grow cells in the lab to investigate effects of epigenetic changes on function. And GTeX allows researchers to see the impact of gene differences on gene expression in any tissue in the body.

That could be a big step forward in understanding how changes in genes might cause many diseases, including ME/CFS.

Davey Smith clearly has a very sharp, innovative mind. And the good news is that’s he’s likely to be bringing his smart ideas to bear on ME/CFS, through the CMRC’s Grand Challenge, which holds its first meeting in April.

Disclaimer: This blog is my take on Professor Davey Smith’s excellent talk, based on the YouTube video. The official summary of his talk, written by Emily Beardall with Action for ME, and approved by Davey Smith, is available to download here.

Simon McGrath tweets on ME/CFS research:

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{ 16 comments… add one }

  • Sasha February 26, 2016, 6:25 am

    This is fascinating, @Simon, thank you.

    This bit especially intrigued me:

    Simon

    Epigenetic changes could play a role in ME/CFS, and Davey Smith said that there was an intriguing way scientists could determine this — though it’s not yet been done this way.

    If scientists can identify epigenetic changes that are linked to a disease like ME/CFS, they could potentially use new technology to grow cells in the laboratory with those epigenetic changes, and see if they function differently.

    If so, those changes may be driving the disease, and if not, they’re probably just irrelevant passengers along for the ride, as with vitamin E’s link with coronary heart disease. Davey Smith called this possible approach ‘very exciting’.

    It relies on use of some very clever technology to turn blood cells into whatever cell types researchers want to study, even neurones. The NIH’s new ME/CFS study plans to use a similar approach to grow and investigate neurones in the lab, starting off with cells from patient blood (though they won’t be looking at epigenetics).

    Very interesting, and I'm glad that you flagged up a positive in the NIH study – we've (inevitably and appropriately) focused so much on the problems with that study that we're in danger of losing sight of the fact that it's 80% brilliant.

  • Sasha February 26, 2016, 6:30 am

    This is excellent, @Simon – I'm going to print it off and get all this omics stuff into my head properly. I think George Davey Smith and the Grand Challenge are going to be major forces in ME/CFS research and I want to understand this research as it goes forward.

    Do you know if we'll get any sort of reportage or summary from the April meeting?

  • Simon February 26, 2016, 6:46 am
    Sasha

    This is excellent, @Simon I think George Davey Smith and the Grand Challenge are going to be major forces in ME/CFS research and I want to understand this research as it goes forward. Do you know if we'll get any sort of reportage or summary from the April meeting?

    I expect we'll hear a lot more in April, and hope we'll hear more specifically about George Davey Smith and the Grand Challenge very soon.

    I have simplified things a lot, hope I haven't lost any of the essential details.

    Sasha

    This is fascinating, @Simon, thank you.
    This bit especially intrigued me:

    It relies on use of some very clever technology to turn blood cells into whatever cell types researchers want to study, even neurones. The NIH’s new ME/CFS study plans to use a similar approach to grow and investigate neurones in the lab, starting off with cells from patient blood (though they won’t be looking at epigenetics).

    To go into some of the boring details, the NIH are collecting blood stem cells from patients while Davey Smith is suggesting a slightly different route. Whenever people take blood samples in big population studies, he's advocating making some of those blood cells immortal to create cell banks (the EBV virus can be used to transform white blood cells into immortal lymphoblastoid cell lines – it's the lymphoblastoid cells, rather than blood stem cells, that will then get turned into other tissue types).

  • Simon February 26, 2016, 7:11 am

    So here's some neat transcriptomics stuff – in NIH Director Francis Collins' blog – that could well be applied to mecfs
    Lyme Disease: Gene Signatures May Catch the Infection Sooner |

    An NIH-supported team recently uncovered a unique gene expression pattern in white blood cells from people infected with the Lyme disease-causing bacterium Borrelia burgdorferi [1]. This distinctive early gene signature, which persists after antibiotic treatment, is unique from other viral and bacterial illnesses studies by the team.

    It would be interesting to apply this to prospective studies of EBV/glandular fever: does the gene signature long-term still look like infection even after people have recovered? This Lyme study found no difference in long-term signature between those that recovered and those that did not.

  • Sasha February 26, 2016, 7:32 am
    Simon

    So here's some neat transcriptomics stuff – in NIH Director Francis Collins' blog – that could well be applied to mecfs
    Lyme Disease: Gene Signatures May Catch the Infection Sooner | NIH Director's Blog
    [/URL]

    It would be interesting to apply this to prospective studies of EBV/glandular fever: does the gene signature long-term still look like infection even after people have recovered? This Lyme study found no difference in long-term signature between those that recovered and those that did not.

    Very interesting question. A post-EBV control group would seem to make much more sense than a post-Lyme group for the NIH ME/CFS study, given that the Dubbo studies showed that 11% of PWEBV go on to get ME/CFS.

  • voner February 26, 2016, 8:42 am

    Simon,

    thank you. I have read about the subject numerous times and have never come away with a complete understanding. your blog clears up a few things for me.

    The Light's Gene expression work has always intrigued me. any idea how big the patient sample size would have to be to do a valid replication study.?

  • Simon February 26, 2016, 9:09 am
    voner

    The Light's Gene expression work has always intrigued me. any idea how big the patient sample size would have to be to do a valid replication study.?

    Not sure: they are focusing in on a relatively few genes highlighted by earlier studies, and with a strong plausible reason for being involved (ie not looking at transcriptomics approach, to see what's up as in the Lyme study) so wouldn't need a massive one, I suspect. They apprarently used 150 people in the study: not sure if that's just patients or includes controls too.

  • JaimeS February 26, 2016, 10:42 am
    Simon

    For example, rats exposed to the main psychoactive component of cannabis during adolescence have offspring that are more likely to get addicted to heroin. And epigenetic changes — not changes to the DNA — are responsible for this. It’s less clear as to whether or no human epigenetic changes are passed on.

    While I know that studies with rats aren't reliable for human research, you'd think that heritability follows similar rules in higher-level organisms, since it's following straightforward chemical and physical laws. Am I missing something?

    Simon

    That’s because diseased liver cells have undergone epigenetic changes, and when diseased liver cells divide, said Davey Smith, they produce two sick cells: the new cells don’t revert to being healthy liver cells.

    Maybe he's just speculating, or maybe he's talking about rat livers only, or liver cells in vitro, but it does seem that he's discussing epigenetics in human beings…

    -J

  • A.B. February 26, 2016, 12:16 pm

    Thanks Simon. Another great article, as usual.

  • Bob February 26, 2016, 12:51 pm
  • Simon February 26, 2016, 1:04 pm
    JaimeS

    While I know that studies with rats aren't reliable for human research, you'd think that heritability follows similar rules in higher-level organisms, since it's following straightforward chemical and physical laws. Am I missing something?

    Turns out there are major differences in epigenetic mechanisms between rodents and people, so doesn't necessarily follow. There's some evidence of inheritance in humans, particularly where whole populations starved:

    Epigenetics 101: a beginner’s guide to explaining everything | Cath Ennis | Science | The Guardian

    Studies of humans whose ancestors survived through periods of starvation in Sweden and the Netherlands suggest that the effects of famine on epigenetics and health can pass through at least three generations. Nutrient deprivation in a recent ancestor seems to prime the body for diabetes and cardiovascular problems, a response that may have evolved to mitigate the effects of any future famines in the same geographic area.

    JaimeS

    Maybe he's just speculating, or maybe he's talking about rat livers only, or liver cells in vitro, but it does seem that he's discussing epigenetics in human beings…

    Sorry that waasn't clear: he was talking human liver cells there (though I added the point about cirrhosis to emphasis that disease continued even after causal factors were removed).

  • JaimeS February 27, 2016, 6:28 am
    Simon

    Turns out there are major differences in epigenetic mechanisms between rodents and people

    :balloons:SCIENCE.:thumbsup:

    That is really weird and cool, @Simon!

    -J

  • Sean March 1, 2016, 8:45 pm

    Another great write up, Simon. :thumbsup:

    Still wrapping my head around it all. The differences between rodents and humans is a good reminder of the potential pitfalls in relying too much on animal models. Yeah, we share a lot with other species, but not everything, and those differences can be critical. :nerd:

  • MeSci March 4, 2016, 12:53 pm
    Simon

    To go into some of the boring details, the NIH are collecting blood stem cells from patients while Davey Smith is suggesting a slightly different route. Whenever people take blood samples in big population studies, he's advocating making some of those blood cells immortal to create cell banks (the EBV virus can be used to transform white blood cells into immortal lymphoblastoid cell lines – it's the lymphoblastoid cells, rather than blood stem cells, that will then get turned into other tissue types).

    Simon! Science is NOT boring! :)

  • flybro September 26, 2016, 1:55 pm

    I'm sure wessley was trying to push into epigenetics.

    I did a google search on epigenetics and wessely, and got this..

    Some results may have been removed under data protection law in Europe. Learn more

    I wonder if that means wessley has put up a fight to get stuff taken down?

  • Manganus December 24, 2016, 2:57 pm
    flybro

    Some results may have been removed under data protection law in Europe. Learn more

    I wonder if that means wessley has put up a fight to get stuff taken down?

    Nope, …not at all! 😉
    That's the standard phrase for search results involving humans.