silenced genes

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silenced genes

Postby dignan » Fri Nov 30, 2007 8:18 pm

I think this type of knowledge could have implications for scientists studying MS.

Duke Scientists Map 'Silenced Genes'

AP - Remember biology class where you learned that children inherit one copy of a gene from mom and a second from dad? There's a twist: Some of those genes arrive switched off, so there is no backup if the other copy goes bad, making you more vulnerable to disorders from obesity to cancer.

Duke University scientists now have identified these "silenced genes," creating the first map of this unique group of about 200 genes believed to play a profound role in people's health.

More intriguing, the work marks an important step in studying how our environment - food, stress, pollution - interacts with genes to help determine why some people get sick and others do not.

"What we have is a bag of gold nuggets," lead researcher Dr. Randy Jirtle said about the collection of "imprinted" genes. The team's findings were published online Friday by the journal Genome Research.

Next comes work to prove exactly what role these genes play. "Some will be real gold and some will be fool's gold," Jirtle added.

Usually, people inherit a copy of each gene from each parent and both copies are active, programmed to do their jobs whenever needed. If one copy of a gene becomes mutated and quits working properly, often the other copy can compensate.

Genetic imprinting knocks out that backup. It means that for some genes, people inherit an active copy only from the mother or only from the father. Molecular signals tell, or "imprint," the copy from the other parent to be silent.

Jirtle compared it to flying a two-engine airplane with one engine cut off. If the other engine quits, the plane crashes. In genetic terms, if one tumor-suppressing gene is silenced and the active one breaks down, a person is more susceptible to cancer.

Only animals that have live births have imprinted genes. It was not until 1991 that it was proved that humans had them. Until now, only about 40 human imprinted genes had been identified.

The Duke map verified those 40 and identified 156 more. Researchers fed DNA sequences into a computer program that decoded patterns pointing to the presence of imprinted genes instead of active ones.

Many of the newly found imprinted genes are in regions of chromosomes already linked to the development of obesity, diabetes, cancer and some other major diseases, the researchers reported. One, for example, appears to prevent bladder cancer. A second appears to play a role in causing various cancers and may affect epilepsy and bipolar disorder.

Scientists had thought imprinted genes would account for about 1 percent of the human genome. While scientists must double-check that the newly identified ones are truly silenced, the new map matches that tally.

"It's a fascinating paper," said Dr. Nora Volkow, director of the National Institute on Drug Abuse. Volkow praised the new mapping method for speeding the slow discovery of these genes.

She said finding which genes are imprinted is important for a bigger question: How do behavioral or environmental factors tip the balance for someone who is genetically predisposed to a health problem?

Previous work by Jirtle and others shows the environment can reprogram how some genes operate, making them speed up or slow down or work at the wrong time. In a groundbreaking 2003 experiment, Jirtle fed pregnant mice different nutrients to alter the coat color of their babies. The feed affected chemical signals that control how hard a certain gene worked, determining when the babies had yellow coats like mom or brown ones.

"It's not just about the sequence of your genes, but how that sequence is turned on and off by environmental exposures that is likely to determine whether you will be healthy," Volkow said. Imprinted genes "are likely to be particularly susceptible to environmental factors."

Sometimes imprinting goes awry before birth, leaving a normally silenced gene "on" or silencing one that should not be. Faulty gene imprinting leads to some devastating developmental disorders, such as Angelman syndrome, which causes mental retardation.

Now a question is how imprinting may be changed to reactivate an imprinted gene after birth.

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Postby mormiles » Sat Dec 01, 2007 6:23 am

Hi dignan, Epigenetics is fascinating. Since you're interested, try googling it coupled with MS, neuro, myelin, chronic, inflammatory, or any of the other usual terms you use when you investigate. You might also couple it with "methylation" for a big eye-full. Happy googling,
Joyce (aka cypriane)~caregiver and advocate in Dallas for Steve (SPMS)----"Enter through the narrowgate..."
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Postby dignan » Sat Dec 01, 2007 11:53 am

Mormiles, I agree about epigenetics. If you haven't checked them out already, I think you might find some of the posts from BioDocFl on epigenetics to be really interesting. Check out his posts in these threads:
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Postby dignan » Tue Dec 11, 2007 12:09 pm

This is about cancer research, but it pertains to silencing genes. Maybe it will have implications for MS day...

Keeping at-risk cells from developing cancer

Researchers at Johns Hopkins have discovered that cancers arising from epigenetic changes - in this case the inappropriate activation of a normally silent gene - develop by becoming addicted to certain growth factors.

Reporting online in next week’s Early Edition of the Proceedings of the National Academies of Sciences, the team shows that blocking this “addiction” can greatly prevent cancer growth.

“If this is translatable to people, it could be really exciting,” says Andrew Feinberg, M.D., professor of medicine, oncology and molecular biology and genetics and director of the Epigenetics Center at Hopkins. “It means we might be able to do something about at-risk cells before cancer develops, and treat these cells biochemically and specifically, rather than using current drugs that are nonspecific and kill everything in their path.”

The gene for growth factor IGF-II (insulin-like growth factor two) is one of several in the human genome that is controlled by imprinting - where one of the two copies of the gene is turned off, depending on which parent it came from. Normally, the IGF-II gene from your father is turned on and the one from your mother is turned off. Loss of this imprinting causes the activation of the maternal copy, leading to activation of both copies of the IGF-II gene, which has been associated with a fivefold increased frequency of intestinal tumors in people.

The Hopkins team tested mouse cells with imprinting intact, which have only one copy of IGF-II activated, and compared them to cells that had lost imprinting and have both copies of IGF-II activated. They found that normally imprinted cells respond to normal doses of growth factor and recover within 90 minutes. However, cells that had lost imprinting were activated by the smallest doses and continued to stay activated for more than 120 minutes.

“It’s like they were on a hair trigger, which was totally counterintuitive to what we might have predicted,” says Andre Levchenko, Ph.D., an assistant professor of biomedical engineering at Hopkins and co-director of the study. “You would expect in cells that have lost imprinting, and therefore have twice the amount of gene product, that it would take higher doses to activate the cell. In fact, the cell becomes hypersensitized while having too much IGF-II around.”

The researchers then wondered if blocking the cells’ response to IGF-II could block cancer growth in animals. Mice that develop colon cancer were given a drug that specifically blocks a cell’s ability to respond to IGF-II. These mice developed 70 percent fewer precancerous lesions than mice without treatment.

“Finding the molecular mechanism behind cancer development allowed us to use a specific drug to actually take care of these risky cells before the animal developed cancer,” says Feinberg. “It’s making us think about cancer prevention in a whole new way.”
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Postby BioDocFL » Tue Dec 11, 2007 3:57 pm

I'm very curious to find out what drug they used on the rats. I am thinking a general approach they may have tried is to keep the cell's S-adenosylmethionine high so that there are plenty of methylation precursors around to help keep the DNA and histones methylated, and thereby silence some of the copies of the gene. This is similar to the possible loss of epigenetic control in female cells of the active and inactive X chromosomes I have hypothesized about before.
Cancer researchers used to speak of Knudsen's 'Two Hit' hypothesis, i.e. that for a cell to become cancerous, the cell needs two genetic mutation events, such as a mutation knocking out a tumor suppressor gene and another mutation kicking in overexpression of another gene, like a signalling cascade kinase. Now I think cancer researchers are starting to think of an epigenetic event as being one (or perhaps both) of the 'Two Hits'. If you allow that an epigenetic event is a possibility in the cancer process, then activation of a latent virus or invasion by a virus could lead to the viral DNA and proteins taking up a lot of the epigenetic precursors (such as S-adenosylmethionine or acetyl-CoA) as the cell tries to silence them like any other genes. But this could over tax the cell's control of its own DNA, leading to activation of the previously silenced copies of genes. This could show a route by which a viral infection could eventually lead to cancer. And our little friends EBV or CMV or other latent viruses could do the same in a lead up to autoimmune diseases. I still don't think we can say for sure that EBV, for example, leads to a bout of a disease like MS or that the latent EBV genes just happen to become activated because of the cell's loss of epigenetic control. Cause or effect?

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Postby Lyon » Tue Dec 11, 2007 4:33 pm

Last edited by Lyon on Thu Dec 01, 2011 1:40 pm, edited 1 time in total.
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Postby dignan » Tue Dec 11, 2007 9:48 pm

Wesley, I don't mean to brag here, but I think I actually understood most of your post! I hope whatever substance these researchers used in their study is an existing drug, that could speed things up a bit...or slow them down if its patent is expiring soon. I take that back, I don't know what I hope.
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