Human Epigenome Project

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Human Epigenome Project

Postby dignan » Fri Dec 16, 2005 11:38 am

Another international genetics effort brewing that has implications for MS research.

Forget mutations: geneticists are hunting for subtler changes to DNA.

December 16, 2005 - Nature - Geneticists are brewing plans for a collective effort, loosely patterned on the Human Genome Project, that would map subtle changes in DNA. Some say that these changes are just as important to our understanding of disease as straight mutations.

As many as half of the genetic alterations that cause cancer, for example, may be 'epigenetic' changes rather than mutations, says Stephen Baylin, a tumour biologist at Johns Hopkins University in Baltimore, Maryland, who is involved with the proposal.

In mutations, letters of the genetic code can be changed or stretches of DNA deleted. But in a common epigenetic change, for example, a small molecule simply latches on to DNA in a process called methylation. This does not change the genetic sequence, but it can still shut a gene down.

The plan for a Human Epigenome Project, backed by dozens of scientists, is published on 15 December in the journal Cancer Research1. Supporters say that have not encountered much resistance. But they add that this is probably because their proposal does not yet come with a price tag.

Organizations looking into the project, including the US National Cancer Institute and the American Association of Cancer Research, have not yet committed any funds.

"Nobody is denying that the epigenome project would be useful," says Michael Stratton, who heads a cancer genome project at the Wellcome Trust Sanger Institute in Hinxton, UK. "The constraint is always the cost."

Researchers have only realized the importance of epigenetic changes in the past five years, says Baylin. In addition to cancer, the changes are known to underlie other diseases, including neurological disorders. And stem cells have been found to rely heavily on epigenetic processes, turning genes on and off as they divide and mature.

Each type of human cell comes with its own set of epigenetic settings. Understanding those, say proponents, would set the stage for understanding what goes wrong during disease, and would help select genes to target with drugs.

"You can go into the dark parts of the genome that you would never have imagined would yield drug targets and find things," says Stratton.

The technology for detecting methylation has advanced rapidly in the past few years. Several epigenetic projects are under way, and the Sanger Institute and others are running a pilot project looking at individual chromosomes. The Human Epigenome Project would coordinate these efforts and set research priorities.

The proposal comes on the heels of an announcement earlier this week that the US National Institutes of Health will allocate US$100 million in pilot funds for The Cancer Genome Atlas, a project that aims to catalogue the genetic changes associated with cancer (see 'Big money for cancer genomics').

This project will include an epigenetics component. But experts say there is much more scope for work in epigenetics than could be encompassed by the cancer atlas.

"If you went at it full scale, it would be as big or bigger" than the cancer project, says Baylin. "It could get huge." ... 12-13.html
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Postby BioDocFL » Mon Dec 19, 2005 8:25 am

"Researchers have only realized the importance of epigenetic changes in the past five years, says Baylin."

This is a completely wrong statement! Researchers have been looking at epigenetics and its potential effect in disease processes for many years. The histone packaging of DNA was determined 30 years ago and it was immediately realized that it could affect the expression of the underlying genes. The statement totally ignores the work of David Allis and many others on determining the 'histone code'. The statement totally ignores the work of Rudolph Jaenisch and many others on X inactivation. It ignores the work of Alexander Rich and many others on the potential effects of alternate DNA structures that can occur based on DNA modifications. The statement totally ignores the relationship of MeCP2 (a methylated DNA binding protein) and its relationship to Rett's syndrome. There are many areas of epigenetics and their potential relationship to diseases. Heterogeneous nuclear RNA is another area that could be related to differential expression of genes. And then there is the area of alternate splicing.

It is very disturbing to see someone of supposed importance in getting NIH and others finally going in a good direction, having a mindset with such a short reference time frame as to what has been done. It makes me wonder who he is referring to as 'researchers'. By researchers does he mean those people who have had a bias for genetic or immunological explanations of diseases? Is he referring to a small clique of researchers, like we talk of politicians as being 'inside the beltway'? Hopefully we can get away from inbred thinking that has stiffled research in new directions because of a bias for genetic or immunlogical explanations.

And when we begin to find more relationships of epigenetics to diseases, are we going to have to wait another 30 years for the 'researchers' to realize that it is the processes that place epigenetic marks on genes that are important? There are already people who have been looking at histone modifications (acetylation, methylation, ubiquitination, etc.), DNA methyl transferases, and chromatin higher order structure, all of which can affect expression of the underlying genes without alterring the DNA sequence.

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