DNA Methylation Modifications Associated with CFS

[catly]

Here's the link to the Solve CFS Initiative webinar with the author of this study, Patrick McGowan.

 

[Gijs]

With all respect i don't think this study will lead anywere for ME.

 

[Bob]

With all respect i don't think this study will lead anywere for ME.

I find this line of research quite interesting, but I think it's in its infancy, in terms of leading to any potential treatments. Also, as with Cytokine research, I think epigenetic abnormalities are probably indicative of down-stream processes rather than the cause of disease. But, having said all of that, the research may give us some unexpected answers or clues to disease process. And, it may lead us towards certain proteins or enzymes that could be inhibited with drugs to improve symptoms. Who knows at this stage. I think this sort of research is better than no research.

 

[Bob]

Here's the link to the Solve CFS Initiative webinar with the author of this study, Patrick McGowan.

Just in case anyone missed catly's post, the video for the latest Solve ME/CFS webinar, with Patrick McGowan re epigenetics, has now been posted:
www.youtube.com/watch?v=QjrBP7MFVPY&feature=youtu.be&list=UUzrFQHNiCc_6AMpw_GpWZOA

 

[MeSci]

I find this line of research quite interesting, but I think it's in its infancy, in terms of leading to any potential treatments. Also, as with Cytokine research, I think epigenetic abnormalities are probably indicative of down-stream processes rather than the cause of disease. But, having said all of that, the research may give us some unexpected answers or clues to disease process. And, it may lead us towards certain chemicals or proteins that could be inhibited with drugs to improve symptoms. Who knows at this stage. I think this sort of research is better than no research.

I understood that epigenetic changes can be inherited. I expect the science has moved on since I first heard about it, but it was being claimed that epigenetic changes acquired by a grandparent had been found to be present in grandchildren. I think an example used was nutritional deprivation during one of the world wars. So, for example, if this caused an epigenetic change that enabled the grandparent to cope with the circumstances, could this perhaps be contributing to the current obesity epidemic, with the grandchildren still being epigenetically adapted to World War-type deprivation and thus especially maladapted to plentiful food availability today? (So why can't they lose the epigenetic change as easily as it was produced? Maybe some can?)

One might assume that paternal epigenetic changes could occur in his offspring, as male gametes are produced during the father's lifetime, whereas in the female line it would skip a generation because girls are born with their full complement of gametes, or at least the precursors to them...or have I misremembered my reproductive biology?

 

[Jonathan Edwards]

I listened to the webinar. Unfortunately, it does not give us much information about the genes they picked out. That I have got from the paper itself, but I would have liked a bit more discussion in the webinar.

What worries me is that the presented Dr McGowan seems to be muddling up the general process of methylation with the methylation changes in individual genes her has found. I agree with DanielBR this study has nothing to do with methylation processes, as studied by Rich

 

[Jonathan Edwards]

I listened to the webinar. Unfortunately, it does not give us much information about the genes they picked out. That I have got from the paper itself, but I would have liked a bit more discussion in the webinar.

What worries me is that the presented Dr McGowan seems to be muddling up the general process of methylation with the methylation changes in individual genes her has found. I agree with DanielBR this study has nothing to do with methylation processes, as studied by Rich van K. I don't think any dietary modifications aimed at methylation would be relevant because we are talking about specific changes in specific cell types in specific genes. Changing diet would be a bit like hoping to make the hair on your head to go from blonde to auburn and your pecs to enlarge while keeping your eyebrows blonde and having less bulk on your biceps or maybe expecting to improve your flower arrangement by putting more water in the vase. It is just at the wrong level of causation. And it is not entirely clear that Dr McGowan gets that!

In other words these methylation changes cannot be altered by drugs or diets that affect methylation. You need to give a drug that alters cell behaviour through receptors or kinases or the usual sort of thing and rely on the cells to methylate specific genes as a result. I cannot see that this approach suggests new sorts of therapy, it just tells us a bit more about how our usual drugs might work.

Like MeSci I was really puzzled by exactly when people think methylation of genes can cause effects. So was my geneticist friend over for the weekend. So we both looked it all up. As far as I can see it works like my next post says. I would be interested if anyone can correct bits I get wrong.

 

[Jonathan Edwards]

My understanding is that in the promoter or regulator regions of genes you have places where a C is next to a G (out of the four nucleotide options C,A,T,G). That makes a CG, which for some reason is called CpG (p for pair?). Interestingly, the other DNA strand, going in the opposite direction will also have a CpG because C goes opposite G and vice versa. The promoter region has stretches that form receptors for activating proteins called transcription factors. If the promoter is heavily covered in methyl groups stuck on the CpGs then activators cannot bind and the gene is not used. If the methyl groups are all taken off to make the promoter 'hypomethylated' it can be activated.

What this seems to mean is that control of gene expression depends on two sorts of effect with different time frames. Minute to minute or hour to hour activating transcription factors (probably inhibitors too, which may complicate things) stick on and come off and control gene usage in the short term. In the longer term cells alter the methylation of their genes to control what genes are allowed to be switched on over periods of weeks, months or years and maybe even centuries (I'll come back to that). This is presumably the main explanation for what we call cell differentiation and maturation. When a stem cell becomes a chondrocyte presumably the gene for make cartilage collagen gets hypomethylated and stays like that through generations of chondrocytes for ever, unless some powerful cytokine signal 'de-differentiates' the chondrocyte to turn it back into a fibroblast.

So methylation is just the long term control of gene expression in an individual it seems. Two questions then come up. Firstly, how does the cell methylate (or demethylate) one gene and not another? This should not be too hard to explain because a methylating enzyme could be towed along by a transcription factor capable of binding to an area still available and forcing the remaining areas for that gene to be demethylated by the enzyme while not letting the enzyme wander off to other genes. What is more puzzling is how methylation can be passed on down cell clones, from chondrocyte to daughter chondrocytes or B cell to plasma cells. When a parent cell divides it makes a new copy of all the DNA so that there is one for each daughter cell. But how does the new DNA copy know which of its CpGs should be methylated? You cannot tell a methylating enzyme just to methylate all the sites that were methylated on the other copy - how would it know? So I think what must happen is this: When the original pair of strands split you have single DNA strands going in opposite directions but, as indicated above, both with a CpG at a particular locus. If we assume that both are methylated what we need is an enzyme that tags along with the DNA polymerase that makes a new backwards strand to fit the forwards strand and vice versa and whenever it meets a methylated CpG it methylates the new pair.

What this would mean is that methylation is actually passed on in cell division just the same as the genes are. There will be different rules for changing methylation during life and changing genes during life (this occurs for antibody genes but not much else) but both can be passed on through many generations. What that means is that methylation CAN be passed on to offsrping, at least potentially. I agree with MeSci that there was evidence that for one or two generations this may happen in humans. I thin kin plants it may be a common thing that passes on adaptations to climate and things like that. Dr McGowan said that methylation was not passed on but I suspect that is not necessarily true.

The idea that the obesity epidemic might be the pay back for starvation in the nineteenth century is then not that implausible. I fear it is wishful thinking but it certainly looks possible to me.

 

[DanME]

I totally agree with your analyses, Dr. Edwards. I want to add another phenomenon, called genomic imprinting. In the germ line chromosomes must be reprinted through methylation and histone modulation as "fatherly" and "motherly". If this process goes wrong during the spermato- and oogenesis, several rare genetic diseases occur, like the Angelman Syndrome (two fatherly imprinted 15 chromosomes, but genetically from the mother and the father) and the Prader-Willi-Syndrome (the opposite, two motherly imprinted 15 chromosomes). It is a rare occurrence of epigenetic heritage.

Other epigenetic heritage (through life events) is discussed in the literature and there is some evidence for it, especially for the starvation hypothesis and in some plants (like tomatoes). But it seems to be a rather rare mechanisms, but not impossible.

Interestingly, I just ve read at Wikipedia, that false epigenetic reprinting could be responsible for homosexuality. Gays could have two "motherly printed" chromosomes from the father and the mother, which are responsible for sexuality and sexual preference and lesbians the opposite. A nice theory, but still unproven.

 

[Cheesus]

Interestingly, I just ve read at Wikipedia, that false epigenetic reprinting could be responsible for homosexuality. Gays could have two "motherly printed" chromosomes from the father and the mother, which are responsible for sexuality and sexual preference and lesbians the opposite. A nice theory, but still unproven.

Off topic, but would bisexual people have? There is no combination for that!

ETA: Just realised that sounded a little aggressive. It was more a rhetorical question to provoke thought than me challenging you for an answer

 

[Jonathan Edwards]

In the germ line chromosomes must be reprinted through methylation and histone modulation as "fatherly" and "motherly". If this process goes wrong during the spermato- and oogenesis, several rare genetic diseases occur, like the Angelman Syndrome (two fatherly imprinted 15 chromosomes, but genetically from the mother and the father) and the Prader-Willi-Syndrome (the opposite, two motherly imprinted 15 chromosomes).

Interestingly, I just ve read at Wikipedia, that false epigenetic reprinting could be responsible for homosexuality. Gays could have two "motherly printed" chromosomes from the father and the mother, which are responsible for sexuality and sexual preference and lesbians the opposite. A nice theory, but still unproven.

I had not caught up with the Prader-Willi story, which shows just how much our traditional ideas of Mendelian rules must be oversimplified. Very interesting. On the other hand the gay story looks to me to involve a dodgy logic step. Motherliness and fatherliness of methylation of autosomal chromosomes is presumably nothing to do with femaleishnes and maleishness since everyone gets both. It ought to be more to do with allelic dose phenomena I think. For the sex chromosomes, or at least Y, it wouldn't apply anyway. I cannot quite get my head around it but it sounds to me like someone is thinking a bit loosely here. I will have to get my geneticist friend on to it.

 

[DanME]

Yes, the step seems to be a bit large and wobbly. But interestingly identical twins have a higher chance to be both gay, but not 100% (in reality 20%, in population just 8%). So the sexual preference cannot be in the genes alone. There must be another factor, like an epigenetic switch or a higher or lower concentration of androgens in one foetus through development. If my understanding of the theory is correct (I just cross read) the authors assume, that we have certain gens, which shield us from androgenic effects during development. Females have a high shielding and males a low shielding. If you get two switched on shielding gens as a male foetus, the chances are high, you will be a gay man and with lesbians the opposite (two switched off shielding gens).

1. William R. Rice, Urban Friberg, and Sergey Gavrilets: Homosexuality as a Consequence of Epigenetically Canalized Sexual Development. The Quarterly Review of Biology, Vol. 87, Nr. 4, Dezember 2012

I think I got us a little of topic. But it is so interesting.

Maybe bisexuality occurs through medium shielding? But on the other hand, straight people would have a medium shielding anyway.

 

[MeSci]

But interestingly identical twins have a higher chance to be both gay, but not 100% (in reality 20%, in population just 8%).

Was this study done with separated identical twins, and were they compared with non-identical twins? This is necessary to control for environmental factors.

 

[MeSci]

Re the stages at which methylation might occur during development (thinking about maternal inheritance, etc.) I wondered whether congenital disorders could be epigenetic (sorry, Prof Edwards ) methylation-related.

A quick search found this paper which says yes.

So conditions in the womb can cause epigenetic changes in a foetus.

When is the genotype/epigenotype of the female foetus's gametes determined? Maybe I have the answer somewhere in my brain but can't find it!

Thank you very much for your message #28, @Jonathan Edwards. It took a while to hammer it into my foggy brain but I got there. Fascinating.

 

[DanME]

I don't know. But what could environmental factors be after birth? Homosexuality is as old as mankind, appeared in all cultures and it occurs in nearly all mammals. So food, chemicals, cultural settings etc. cannot be responsible. It must be in genetics, epigenetics or in hormonal changes through pregnancy.

 

[MeSci]

I don't know. But what could environmental factors be after birth? Homosexuality is as old as mankind, appeared in all cultures and it occurs in nearly all mammals. So food, chemicals, cultural settings etc. cannot be responsible. It must be in genetics, epigenetics or in hormonal changes through pregnancy.

I was thinking more about the family environment. I'm not saying that I think this is the case, just that it needs to be controlled for in research such as twin studies.

 

[Bob]

I can't remember where our discussions re diet and meditation originated (were they mentioned in the abstract of the paper?) But Dr Gowan contradicts the potential of diet etc to easily change methylation, in the video at 38.52.

What worries me is that the presented Dr McGowan seems to be muddling up the general process of methylation with the methylation changes in individual genes her has found. I agree with DanielBR this study has nothing to do with methylation processes, as studied by Rich van K. I don't think any dietary modifications aimed at methylation would be relevant because we are talking about specific changes in specific cell types in specific genes. Changing diet would be a bit like hoping to make the hair on your head to go from blonde to auburn and your pecs to enlarge while keeping your eyebrows blonde and having less bulk on your biceps or maybe expecting to improve your flower arrangement by putting more water in the vase. It is just at the wrong level of causation. And it is not entirely clear that Dr McGowan gets that!

Dr Gowan does discuss changing methylation for individual genes at approx 35.30 in the video.

In other words these methylation changes cannot be altered by drugs or diets that affect methylation. You need to give a drug that alters cell behaviour through receptors or kinases or the usual sort of thing and rely on the cells to methylate specific genes as a result. I cannot see that this approach suggests new sorts of therapy, it just tells us a bit more about how our usual drugs might work.

And he talks about the future possible directions of his research at 37.00 which I think is quite interesting. (e.g. he discusses the potential of using the research to identify biological markers for ME/CFS, and subtyping.)

 

[DanME]

Re the stages at which methylation might occur during development (thinking about maternal inheritance, etc.) I wondered whether congenital disorders could be epigenetic (sorry, Prof Edwards ) methylation-related.

A quick search found this paper which says yes.

So conditions in the womb can cause epigenetic changes in a foetus.

When is the genotype/epigenotype of the female foetus's gametes determined? Maybe I have the answer somewhere in my brain but can't find it!

Thank you very much for your message #28, @Jonathan Edwards. It took a while to hammer it into my foggy brain but I got there. Fascinating.

The genotype of the female gametes is determined, when the female foetus is 12 weeks old. Women are born with fully developed gametes (men are not), which are stored at the ovary till puberty. Recently it was discovered that the adult woman can create sometimes new eggs, if necessary. I have not found, when the chromosomes are imprinted as "motherly".

 

[A.B.]

I don't know. But what could environmental factors be after birth? Homosexuality is as old as mankind, appeared in all cultures and it occurs in nearly all mammals. So food, chemicals, cultural settings etc. cannot be responsible. It must be in genetics, epigenetics or in hormonal changes through pregnancy.

There is a species of birds that becomes homosexual when exposed to mercury.

http://www.nature.com/news/2010/101201/full/news.2010.641.html

Mercury also binds to methyl groups.

 

[DanME]

There is a species of birds that becomes homosexual when exposed to mercury.

http://www.nature.com/news/2010/101201/full/news.2010.641.html

Mercury also binds to methyl groups.

Wow, I have never heard about this phenomenon. And it doesn't make them just gay, but monogamous as well (which Ibises are usually not). I especially liked the last paragraphs:

"However, Frederick and Köhler both caution that the findings cannot simply be extrapolated to other species, even of birds. "Their behaviour may be less fragile and more robust to methylmercury," says Köhler.

Frederick is concerned that "people will read this and immediately jump to the conclusion that humans eating mercury are going to be gay. I want to be very explicit that this study has nothing to say about that," he says."