Folate And Methylation - (Mar/31/2005 )

Hi Fellow Forumers,

I was wondering if people have had experience and will share their views with studying the effects of Folate on DNA methylation?

A question I would like to ask in particular is can folate affect histone methylation as well?

We are changing tack and figure studies in folate metabolism maybe the next wave in epigenetic research.

Cheers

Nick

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Hi Nick,

There are lot of publications on folate and DNA methylation. Certainly folate availability affects DNA methylation. Histone methylation? interesting and probably. But first you have to rule out the possibility of secondary histone methylation caused by DNA methylation.

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yeah I have found many publications on the effects of folate and DNA methylation, there isn't hard evidence of a direct link it seems.

Be interesting to know if it can also affect histone methylation by the same mechanism.

But what does come first? DNA methylation? Histone Deacetylation? or histone methylation?? Chicken and Egg question!

Nick

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hi

i came across many paers talking about methyaltion and folate

i was intersted in one in particular that explains the role of abnormal

methyaltion in non-disjunction , what i have seen from it tthat abnormal

DNA methylation comes first followed by histone deacetylation


here is the paper hope it well be usfull to u

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thanks lulu, much appreciated.

Nick

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hi nick

after you read the paper tell us whats your openion ,,,is histone

deacetylation the first step or abnormal DNA methylation ????

im looking for more recent papers on the subject and illustrating diagrams

i well tell you if i found anything new

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thanks lula,

i'll look into that paper, we are in the process of applying for a march of dimes research grant and we were thinking of putting folate in to make the grant more sexy.

There is a great paper showing in-vitro methylation by stirzaker et al in 2004. showing that DNA methylation seeding is able to trigger histone deacetylation, histone methylation and MBD recruitment.

Cheers

Nick

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Hi Nick,

one of the most interesting problems in folate - DNA methylation subsystems relation i've seen - it is so called THE METHYL TRAP in the form of not metabolised pool of 5 met THF....the last can appear with defficiancy of B12 in the cell not supporting transfer of methyl group from folate system into Met cycle which methylates DNA....
Some theoretical (not only) conclusions:
The Methyl trap occuarance can show (may be not neccesarrily under some condition, but usually) the leakage of the one carbon units to form SAM and finally the sharp consequance - the DNA global hypomethylation when there is not enough of substrate - methyl....if there appear some results about methyl trap in folate system and weaker than usual methylation of histones - it';s great...
I'm studying (theoretically) those systems responsible for DNA methylation for a long time- starting from the origin of methyl carbon - so called 1-carbon units SER input or the branch of glycolysis forming Serine, Met intake, choline system....and ending at- DNA methylases
and I suppose this is the biggest SCANDAL - there is no normally described full system of one carbon units (exeption is of course the global map of biochemical pathways but anyone must look at this for a long time to collect everything about CH3 from different corners of this map)
even today studying different maps of folate pathways or the map used in methyl (nutrition) experiment described at famous conference i was shocked - they are insufficient ...of course the reason is complexity of information...and the genettics is not only the geography of roads, rivers......
so one of the the tasks for DNA METHYLATION SOCIETY (and not only for them) - to describe in a normal shape about 100 carriers and supporters of C(H3) until they appear on DNA and Histones, becouse theoretically any chain damage can result the last steps...interesting problems is not only The methyl trap and methylation level but for example - high (low) rate of glycolysis ( and the great pool of Ser), B12 defficit, the methyl trap and level of methylations...
Good luck

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Hi Urba,

thank you for your reply, and you are indeed correct to say that there are a whole host of pathways that could lead to one carbon metabolism, the folate cycle is only one of them, many feed into the folate cycle and should be taken into account. I wholly agree with you that it is a bit simplistic to only look at the methyl trap as other the accumulated metabolites could be shunted into another pathway.

However, it's tantalising to see that epigenetic markers can be modulated through diet. How is the million dollar question. I guess it is just a wait and see what happens.

nick

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Honourable Nick,
It's a great pleasure for my friends and me to discuss Your message. Thanks.
I'm not the experimentator, but only the theoretitian sitting in libraries, internet databases...building the general theory of the malignant growth like The Puzzle from thousands facts sometimes contradictionary. I'm trying to know more and more theoretical facts and fit them and if my opinion and conclusions will promote experimental job - i'm happy because the theory without experimetal confirmation is only theory.
I play chess not looking at them, but those problems are much more difficult...till histones are not deeply enough studied too.
Very interesting question could be formulated first - at theoretical level - could really some special nutrition type affect methylation process?
There are some experimental results with methyl defficient diet used for rats:
it was started i remember in 19seventy. On the first weeks there was observed total DNA hypomethylation, later on 50 week - malignant foci in rat liver...SAM usage helped....When I've read this for the first time - I was really in the shock - this stresses and prooves the key role of one carbon units pool responsible for methylation processes too...but it was in 1989 and I've discussed those questions in leading institutes in Vilnius, Moscow, St.Petersburg, Kiev, Minsk, Amsterdam having not so strong theoretical puzzle reconstructive model when comparing with the last improved one...but I was supported by advices, opinions to continue theoretical palace building...and I was lucky to rise the discusion...
The methyl defficient diet and liver cancer is discribed for example on
http://lpi.oregonstate.edu/infocenter/othernuts/choline/
it was the first text from 104 000 obtained using the Google search machine -:

Cancer

In rats, dietary choline deficiency is associated with an increased incidence of spontaneous liver cancer and increased sensitivity to carcinogenic chemicals. A number of mechanisms have been proposed to explain the cancer promoting effects of choline deficiency: a) choline deficiency causes liver damage and regenerating liver cells are more sensitive to the effects of carcinogenic chemicals, choline deficiency results in decreased methylation of DNA, resulting in abnormal DNA repair, c) choline deficiency results in increased oxidative stress in the liver, increasing the likelihood of DNA damage, d) choline deficiency may stimulate changes in the programmed cell death (apoptosis) of liver cells, contributing to the development of liver cancer, and e) choline deficiency activates the potent cell signaling molecule, protein kinase C, which creates a cascade of effects that are still being investigated (2,4). The implications for choline deficiency on human susceptibility to cancer remain unclear.

One more:

Carcinogenesis, Vol 5, 1367-1370, Copyright © 1984 by Oxford University Press

ARTICLES
The induction of liver cancer by dietary deficiency of choline and methionine without added carcinogens

AK Ghoshal and E Farber

Fischer 344 male rats fed a choline-methionine deficient diet for from 13 to 24 months developed a 100% incidence of putative preneoplastic hepatocyte nodules and a 51% incidence of hepatocellular carcinoma. The addition of 0.8% choline chloride completely prevented the development of both the nodules and the cancer. The diet contained no added known carcinogen.

and so on... extremly interesting and important results!

The question You rise - The folate system connection with methylation systems is the one but very important chain in all the roads of the one carbon units methabolise till reach DNA...there are 9 different forms of folate and 27 enzyms regulating them (in human less) ... theoretically any damage of any could affect methylation style...so, it's possible to find hundreds of direct reasons on all the pathways and thousands of their pairs....finishhing on the last hot point - direct methylathion - methylases...of course it's clever to start with some methylases...
but when studying DNMT I, DNMTIIIa, DNMTIIIb there were found contradictory results...and returning to susbstrate - methyl source and the accident somwhere in the middle of the road -question because the results using methyl defficient diets and rats exists it is neccesarry...
Sorry, for some hot remarks - few days ago my supporter Gediminas - plays chess too - gave me adwice participate in some forum - not only the book writting...I'l try to study this more deep..I suppose we need strong discussion of theoreticians - who only reads and compares lots of articles-before trying formulate some opinions useful for experiments
Good Luck and good strike

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