News on demethylation - PNAS - article by Zhang et al (Mar/29/2007 )

Hi,

any comments on this article?

Active tissue-specific DNA demethylation conferred by somatic cell nuclei in stable heterokaryons.Zhang F, Pomerantz JH, Sen G, Palermo AT, Blau HM.
*Baxter Laboratory in Genetic Pharmacology, Departments of Microbiology and Immunology, and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305-3175.

DNA methylation is among the most stable epigenetic marks, ensuring tissue-specific gene expression in a heritable manner throughout development. Here we report that differentiated mesodermal somatic cells can confer tissue-specific changes in DNA methylation on epidermal progenitor cells after fusion in stable multinucleate heterokaryons. Myogenic factors alter regulatory regions of genes in keratinocyte cell nuclei, demethylating and activating a muscle-specific gene and methylating and silencing a keratinocyte-specific gene. Because these changes occur in the absence of DNA replication or cell division, they are mediated by an active mechanism. Thus, the capacity to transfer epigenetic changes to other nuclei is not limited to embryonic stem cells and oocytes but is also a property of highly specialized mammalian somatic cells. These results suggest the possibility of directing the reprogramming of readily available postnatal human progenitor cells toward specific tissue cell types.

They were able to show an active DNA demethylation system while excluding DNA replication or cell division as cause for the demethylation...

The quest for a demethylase is going on...

Krümel

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...great! Theoretically it is possible that there is also a similar system for demethylation, deacetylation... for histones
T.

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First one to find the first DNA demethylase gets to publish in Nature or science!!!!!!!!

@Tharom, there are indeed similar mechanisms for histone demethylation and deacetylation and these have been well characterised, DNA demethylase however has remained very elusive.

Nick

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Thank you very much I was just looking for exactly such a paper, now I can leave the word heritable in my presentation!

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Hi,

I was actually just kinda curious. I'm not too familiar with the concept of nuclear reprogramming, and I was wondering why the absence of DNA replication or mitosis would imply that the demethylation is occuring by a active mechanism?

Could anyone explain?

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Indeed, Szyf's group did identify a demethylase in 1999 and the result was published in Nature. However others seems not be able to reproduce their data which is still a controvisial issue.

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Well, if you have a locus in your cell with an elevated DNA methylation and after several days, no more methylation is found, several possibilities can account for this 'demethylation':
- Mitosis and DNA replication - during DNA replication, methylation information will be present only on the mother strands. Methyltransferases will methylate the newly synthetized strand, but that takes some time and can be supressed (as methylation capacity is lower during dna replication - the folate is needed for the synthesis of purines).
- Active Demethylase - an enzyme demethylating the DNA.
- Passive Demethylation - methyl groups just getting lost.
The problem with all experiments regarding this issue is, that it is hard to disprove the first option. If you can't be sure, that methylation got lost during replication, you can only speculate about demethylation. Methylation is a rather tight bound, so a passive demethylation is unlikely to occur.
There are, like pcrman said, the reports by Moshe Szyfs group. They argue for a role of MeCP2. However, no one has replicated these findings...

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hi cancergeek,

have a look at some of the papers by Santos, Dean and Reik, where they looked at global DNA methylation post fertilisation in the mouse model, there is a good review on it and it showed that demethylation post fertilisation is likely to be an active event because of how rapid it was occuring....as Krumel and pcrman have said Syzf's group claimed to have found the demethylase however other groups have not been able to replicate the findings.

Nick

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Hi guys,

thanks for the answers, they've been pretty helpful. I have one more question which may seem a bit naive. I've been trying to find a good review paper explaining how heterokaryons work, but so far haven't been very sucessful. Could anyone give a quick explanation? Is it an active mechanism in the myoblasts which is acting on the keratinocytes? or are the myoblasts activating an endogenous system in the keratinocytes to reprogram them?

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