New research which shows how genes rapidly switch on and off will challenge existing scientific theories, writes Dick Ahlstrom
SCIENTISTS ARE going to have to rethink old ideas about how our genes are turned on and off to deliver proteins. New research shows genes don't stay either on or off, they rapidly switch back and forth between the two and are constantly reset depending on conditions inside the cell.
"This is unexpected. What you have is a core paradigm shift in how nature is working," says Science Foundation Ireland director general, Prof Frank Gannon.
He was commenting not on behalf of SFI but as a scientist directly involved in the research. He came to SFI from EMBL, the European Molecular Biology Laboratory in Heidelberg and led the research teams involved in the work before taking up his new post in Dublin. Details of the research were published in the journal Nature last Thursday.
The group wanted to understand the complex processes going on inside the cell as genes were switched on and off. They were looking in particular at how the female hormone oestrogen was involved given its importance in breast cancer.
"We were looking at how the oestrogen receptor affects the expression of a gene," Prof Gannon explains. To achieve this they first had to "synchronise" the cells under study, to ensure they were all in the same on-off status, all carrying out the same biochemical processes at the same time.
Synchronisation would allow the researchers working in labs in Germany and at the University of Rennes in France to "see" how things were changing inside the cell, Prof Gannon explains.
The detail they were most interested in related to the process of methylation. Methylation is the switching process that says if a piece of DNA, a gene, is turned on or turned off. Its importance is that while it chemically modifies the DNA, it doesn't change the DNA code permanently.
If methylation occurs then a gene becomes "silent". If the methylation is removed then the gene can once again express its protein.
Being able to do this is essential for life, Prof Gannon explains. Each of our cells holds an entire copy of our DNA but only some of this DNA gets expressed, the rest gets silenced by methylation.
"Downs syndrome happens when there is one chromosome too many and you get an imbalance in the system," he says.
"Women have two X chromosomes and men have one. One of the X chromosomes gets silenced in women to avoid the imbalance. The way that nature silences one of the chromosomes is to put a tag on the DNA called a methylation."
Our DNA includes an important tumour suppressor gene called p53. Researchers have found that the p53 is switched off by methylation in 70 per cent of colon cancer cases, Prof Gannon says. Dr George Reid headed the work in Heidelberg where they followed 50 different proteins in their synchronised cell sample. They were looking at how the methylation changed in response to oestrogen and also how histone, the protein that holds the DNA wrapped up in cells, could prevent or allow methylation to occur.
"We argued if we interfered with the histone, that should break the cycle of events leading to cancer," he explains. "You could stop the whole process by introducing something that was an inhibitor further down the line."
While Dr Reid focused on how DNA was controlled by the histone, the collaborator in Rennes, Dr Raphael Metivier started watching methylation in the synchronised cells.
"The view of the world and every text book says if you methylate something it stays methylated, it is an indelible mark," Prof Gannon says. "We used our concept of synchronising things to see if this was true."
IN FACT THEY realised the process was anything but indelible. "We found that the methylation is added to the DNA then taken off." It binds and then unbinds. "You get a constant reversal of it." There was a logic to this, the idea that there must be some way either to renew the methylation signal or ensure it doesn't change over time, given the essential nature of gene silencing.
"There is in our opinion a double lock. There is methylation and [ the process] also needs the histone code to be right."
This becomes very valuable knowledge because it opens up possible new ways to stop cancers, he believes. "Because we have been able to show it is cycling and changing very suddenly, you have an opportunity to use a drug to affect it," he says.