Turning Genes Off And On: Methylation Process Is Transient, Cyclical And Dynamic

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Turning Genes Off And On: Methylation Process Is Transient, Cyclical

And Dynamic, Not Static As Previously Thought

http://www.sciencedaily.com/releases/2008/03/080305144230.htm

A research project led by Professor Gannon, Director General of

Sciencen Foundation Ireland (SFI), has uncovered new revelations on

possible ways to switch genes on and off that impacts on previous

understandings of the biological process of how cells interpret their

DNA.

Until the research reported in two papers published in the journal

Nature, it had been presumed that in the chemical process of

methylation (when a gene is turned on or turned off) a gene was

stable and unchangeable. However, arising from the findings of this

research group at the European Molecular Biology Laboratory in

Heidelberg in Germany which included Dr. Reid, EMBL Professor

in Heidelberg, it has been shown that this is not the case and that

the methylation process is transient, cyclical and dynamic. This

insight came from an approach of synchronising all cells in a

population such that variations were made visible.

With the sequencing of the human genome the general public has become

very aware that the answer to many diseases lies in our DNA.

Crucially, only some of the total possibility of genes are expressed

in any given tissue. For example, a protein that is active in a nerve

cell is not expressed in the liver. The way in which this is

controlled is a complex area that has attracted much research.

One fundamental controlling factor is whether the DNA is tagged or

modified in the region of a particular gene. This modification

(methylation) is important not only in gene expression but also in

ensuring that there is the right balance in the level of expression

of proteins in different cells. For instance women with two

chromosomes have one of these silenced by the same methylation tag

such that they have one active X chromosome as have men. The

consequences of an excess level of expression is well know, for

instance in Downs Syndrome where an extra chromosome is active.

One paper shows that this is a general phenomenon occurring at many

different genes and in many different cell types. The second paper

arises predominantly from the work of Raphael Metivier, a former Post

Doctoral student of Professor Gannon, carried out in Rennes in

France, which shows a mechanism for this newly described phenomenon.

In the first paper, researchers report that estrogen causes rapid

epigenetic changes in breast cancer cells. The new findings impact

upon our understanding of how cells interpret their DNA and suggest

that epigenetic regulation can affect gene expression immediately and

long-term.

Epigenetic changes to the structure of chromatin -- tightly packaged

DNA - grant or deny access to the molecular machinery that

transcribes DNA and thereby regulate gene expression. One of these

mechanisms is DNA methylation, where a small chemical residue called

a methyl group is added to strategic bases on the DNA. The methyl

group prevents the transcription machinery from docking and thereby

shuts down gene expression.

They found out that methylation marks occur rapidly in breast cancer

cells in response to hormones such as estrogen or drug compounds.

Estrogen withdrawal or treatment with the established anticancer drug

doxorubicin cause the methyl groups to be removed from regulatory

regions of specific genes within tens of minutes in human breast

cancer cells. The treatment sets off a whole cycle of events: initial

demethylation renders silent genes active and subsequent

remethylation shuts them down again. This cycle repeats itself every

1.5 hours.

" We observed that unlike assumed for a long time methylation can act

on a very short timescale. The results challenge our understanding of

epigenetics as a means to regulate gene expression permanently, " says

Sara Kangaspeska, who carried out the research together with

Stride.

" In particular breast cancer is affected by estrogen signalling and

changes in epigenetic control, " says Reid, co-senior author of

the study. " Our next step will be to find small molecules that target

the cyclical methylation processes to elucidate their precise role. "

The two papers were published in Nature, 6 March 2008.

1. Transient Cyclical Methylation of Promoter DNA paper was authored

by S. Kangaspeska, B. Stride, R. Métivier, M. Polycarpou-Schwarz, D.

Ibberson, R.P. Carmouche, V. Benes, F. Gannon & G. Reid. This work

was supported by the EC 6th framework programme grant CRESCENDO and

by the European Molecular Biology Organisation (EMBO).

2. Cyclical DNA Methylation of a Transcriptionally Active Promoter

paper was authored by Raphael Metivier, Rozenn Gallais, Christophe

Tiffoche, Le Peron, Renata Z. Jurkowska, P.

Carmouche, Ibberson, Barath, Florence Demay, Reid,

Vladimir Benes, Albert Jeltsch, Gannon & Gilles Salbert. This

work was supported by funds from the Ministere de l'Education

Nationale de l'Enseignement Superieur et de la Recherche (MENESR),

the Centre National de la Recherche Scientifique (CNRS), the

University of Rennes, the Association pour la Recherche contre le

Cancer (ARC), the Ligue contre le Cancer, and by funding from EMBO

and EMBL.