Nutrition linked to DNA switching

Epigenetics - the how and why of gene switching

It's been a while since my last blog, and that's because I have been following a trail down a very interesting rabbit hole. Recent advances is epigenetics are filling in the gaps in the DNA puzzle. In this blog, I'd like to share what I've learned about how our genes get switched on or off, and the fascinating process involved.
 

If you think back to high school, you may have a vague memory in biology about the difference between DNA and RNA. In recent years DNA has become the celebrity of the two, making headlines as the 'code behind all life.' Some reports have even implied that we've 'cracked the code.'
 

The truth is far more complex, and recently RNA has started to grab the headlines. The RNA molecule's job is assist in the copying or transcribing of a gene, so that proteins can be made. Proteins are the basic building blocks of all bodily functions and cells. So this process is crucial to life.
 

What has now been discovered is that RNA is involved in the silencing of genes.
Scientists have been trying to figure out how the cell knows which genes to silence and when. At any given moment a huge amount of our genetic material remains silent, with only selected genetic material being transcribed.
 

In the two articles below, scientists explain how the body produces specific enzymes to methylate or silence genes. These enzymes attach themselves to specific letters in a DNA sequence, preventing the code from being read, and thus silencing that gene temporarily.
As I've discussed in previous blogs, it seems that a large amount of our non-coding or 'junk' DNA is involved in the signalling of what should or shouldn't be silenced.
 

In a separate pilot study published in the ACNEM Journal (Vol 29, No 3, Nov 2010), researchers found a relationship between methylation and mental illness, including addictions, depression and anxiety. This relationship had been studied previously, however because the genetic mechanisms were not understood the results of previous studies were often sidelined.

Extracts of the study - The Effectiveness of Targeted Nutrient Therapy in Treatment of Mental Illness, a pilot study by Richard Stuckey, MB.BS., DRCOG; William Walsh, PhD; Brett Lambert are quoted below:
 

"A clinical outcome assessment was performed on 567 consecutive patients followed up for one year after initial consultation. The data covered patients interviewed between March 2004 and June 2007. Established diagnoses included Autism, ADHD, Asperger’s, Anxiety, Bipolar Disorder, Depression, Schizophrenia and OCD. All patients had an established verifiable diagnosis and most were receiving conventional pharmacological therapy. Patients were instructed not to change any treatment (pharmacological or physical) unless on the instruction of their usual treating practitioner. Treating practitioners were also informed of the additional targeted nutrient program."

Specifically what the researchers found was that both over and under methylation creates serious behavioural problems.
 

For example over methylation creates a high tolerance to pain, resistance to certain drugs, mood swings, poor sleep patterns, poor dream recall, racing thoughts, poor organisation and alcoholism. In extreme cases these individuals may be treated for ADHA, hyperactivity, depression or bipolar disorder.

Scientists have identified abnormalities in methylation in these conditions. It is also likely that the genes being silenced by the over-methylation are involved in the production of brain chemicals like seratonin, dopamine, oxytocin and endorphins. We know that an imbalance in the production of these brain chemicals may lead to poor focus, despite intelligence and therefore poor performance academically.
 

The natural high and calm our brains are supposed to feel in joyous situations may be blocked for these individuals, leading to seratonin seeking behaviour - a craving for carbohydrates, through eating sugary foods and consuming alcohol.
 

Under methylation is associated with anxiety, low pain threshold, low muscle tone, aversion to sunlight, addictions, perfectionism, obsessive compulsive behaviours, high academic achievement, low social skills, arrogance and competitiveness. In extreme cases it may be associated with sociopathic behaviours.
 

Under methylation may be related to an inability to silence certain genes, leading to too many genes being active at once.

What is exciting about this pilot study, is that the researchers used nutritional therapy to correct the methylation abnormality.
 

"Compounds were individualised for each patient according to the nature of the imbalance, the degree of deficiencies and the age and size of the patient. Doses were well in excess of recommended daily allowances.

Decisions were generally made according to the biochemical profile but in cases where this was indistinct, decisions were made on the clinical diagnosis. Note from the schematic representation of the methylation pathway (see Figure 1) there may appear to be some logic in using methionine, or SAMe, in under-methylators and B3, folate and B12 in over-methylators.

It is noted that ‘over-methylation’ may not necessarily be a literal overactivity of methylation but alternatively a block in the adjacent folic acid pathway. The two enzymes implicated are Methylenetetrahydrofolate reductase and Cathchol-O- Methyltransferase

Patients exhibiting symptoms and pathology correlating with under-methylation were administered Vitamins C and B6, Pyridine-5-Phosphate (P5P), Methionine, Calcium, Zinc and Magnesium.

Those exhibiting symptoms and pathology correlating with over-methylation were prescribed Vitamins B3 (Niacinamide), B6, B12, C and E, P5P, Folic acid and Zinc. Patients exhibiting elevated urinary pyrroles (and symptoms of Pyroluria) were prescribed Vitamins C, B6, P5P, and Zinc, while patients exhibiting Copper/Zinc imbalance were prescribed Zinc alone or in combination with Vitamin C."

I include the results as reported below. What has my interest is that it appears that nutritional deficiency is at the heart of many clinical mental disorders, and may be at the root of the chronic unhappiness that is epidemic in our lives.


Outcome Measures

"The interview process for the treatment program began with 567 patients of whom 492 commenced treatment with 382 complying for 12 months. 110 discontinued for a range of reasons (22.4% non-compliance). 75 of those interviewed did not commence the program and respondents to a questionnaire in this group were assigned to the comparison group. Of the 382 that completed one year of the program, 221 (57.9%) stated major improvement, 91 (23.8%) partial improvement and 70 (18.3%) nil improvement.

It is understood that there are methods to ‘objectify’ improvement by questionnaires designed specifically for some of the diagnostic groups, but there are none that would encompass all the diagnostic groups in this study. The outcomes according to diagnosis are represented in Table 2.
Clinical Notes:

"There was a marked reduction in hospital admissions during the 1st year of treatment as compared with the year prior to nutrient treatment.

"There was a reduction in doses of prescription medication in 22.3% of the patient group. Antidepressants and anxiolitics were occasionally withdrawn but antipsychotics were not.

"Most patients with the best results used a combination of both pharmacological and nutritional interventions.

"The relative percentages of improvement and non-improvement were remarkably similar in each of the three groups."

All of the nutrients supplemented in this study used to be common in our diet thousands of years ago when we hunted and gathered. The rapid transformation of society through farming and later industrialisation has resulted in a modern diet that is inadequate in providing the nutrients we need for health.

It is no coincidence that the artificial and highly processed foods that fill our shelves have been associated with an increase in physical diseases like diabetes, heart disease and cancer. It is now clear that the lack of nutrients in these foods may also be fuelling the mental illness epidemic now gripping the developed world.

Finally, we are starting to understand why - and it is all about the interaction of our environment with our DNA. And what's most exciting is that nutritional therapy can reverse the damage.

Food for thought?

Regards,

LIs


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Mystery Solved: How Genes Are Selectively Silenced
 

ScienceDaily (Oct. 18, 2010) — Our genetic material is often compared to a book. However, it is not so much like a novel to be read in one piece, but rather like a cookbook. The cell reads only those recipes which are to be cooked at the moment. The recipes are the genes; 'reading' in the book of the cell means creating RNA copies of individual genes, which will then be translated into proteins.
 

The cell uses highly complex, sophisticated regulatory mechanisms to make sure that not all genes are read at the same time. Particular gene switches need to be activated and, in addition, there are particular chemical labels in the DNA determining which genes are transcribed into RNA and which others will be inaccessible, i.e. where the book literally remains closed. The biological term for this is epigenetic gene regulation.
 

Among the epigenetic mechanisms which are well studied is the silencing of genes by methyl groups. This is done by specialized enzymes called methyltransferases which attach methyl labels to particular 'letters' of a gene whereby access to the whole gene is blocked. "One of the great mysteries of modern molecular biology is: How do methyltransferases know where to attach their labels in order to selectively inactivate an individual gene?" says Professor Ingrid Grummt of the German Cancer Research Center (DKFZ).
 

Grummt has now come much closer towards unraveling this mystery. She has focused on studying those text passages in the genetic material which do not contain any recipes. Nevertheless, these texts are transcribed into RNA molecules in a controlled manner. "These so-called noncoding RNAs do not contain recipes for proteins. They are important regulators in the cell which we are just beginning to understand," says Ingrid Grummt.
 

In her most recent work, Grummt and her co-workers have shown for the first time that epigenetic regulation and regulation by noncoding RNAs interact. The scientists artificially introduced a noncoding RNA molecule called pRNA into cells. As a result, methyl labels are attached to a particular gene switch so that the genes behind it are not read. The trick is that pRNA exactly matches (is complementary to) the DNA sequence of this gene switch. The investigators found out that pRNA forms a kind of plait, or triple helix, with the two DNA strands in the area of this gene switch. Methyltransferases, in turn, are able to specifically dock to this 'plait' and are thus directed exactly to the place where a gene is to be blocked.
More than half of our genetic material is transcribed into noncoding RNA. This prompts Ingrid Grummt to speculate: "It is very well possible that there are exactly matching noncoding RNA molecules for all genes that are temporarily silenced. This would explain how such a large number of genes can be selectively turned on and off."

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Why Some Genes Are Silenced: Researchers Find Clue as to How Notes Are Played on the 'Genetic Piano'
 

ScienceDaily (May 13, 2011) — Japanese and U.S. scientists in the young field of epigenetics have reported a rationale as to how specific genes are silenced and others are not. Because this effect can be reversed, it may be possible to devise therapies for cancer and other diseases using this information.

The NOVA U.S. public television program described epigenetics as "The Ghost In Your Genes." It is the study of changes in gene expression that occur without changes in DNA sequence. Like keys on a piano, DNA is the static blueprint for all the proteins that cells produce. Epigenetic information provides additional dynamic or flexible instructions as to how, where and when the blueprint will be used. "It corresponds to a pianist playing a piece of music," said Kohzoh Mitsuya, Ph.D., postdoctoral fellow in the School of Medicine at The University of Texas Health Science Center San Antonio.
Article in Science
 

The study by Dr. Mitsuya and colleagues is outlined in the May 13 issue of the journal Science. The team found that a small RNA pathway is required to establish an epigenetic modification -- called DNA methylation -- at a gene that codes for mammalian proteins. DNA methylation adds chemical tags called methyl groups to specific genes, usually silencing their expression.
 

"DNA methylation marks are reversible, so there is great interest in devising therapeutic strategies, for instance in cancer biology, to epigenetically reactivate silenced tumor-suppressor genes or inactivate specific oncogenes in human cancer cells," Dr. Mitsuya, the Science paper's third author, said. The lead author is Toshiaki Watanabe, Ph.D., of the National Institute of Genetics in Japan and Yale University.
 

Environment and cancer
Beyond being reversible, DNA methylation is susceptible to environmental influences. Many cancer biologists now agree that changes in DNA methylation might be as important as genetic mutations in causing cancer. There are far more epigenetic changes than genetic changes found in the majority of cancers, and research into epigenetics is proving to be important to understanding cancer biology.
 

"It is critical to identify the entire complement of factors that affect gene silencing," Dr. Mitsuya said. "This was the rationale behind this study examining DNA methylation in mice that I began in 2004. The study adds information about one set of factors."
A finger on the piano
 

The researchers compared a group of normal mice with a group lacking the small RNA species. The team found that DNA methylation was markedly reduced at one of four genes tested in the small RNA-deficient mice. "This is the first demonstration that small RNAs can act in this way," Dr. Mitsuya said. "It shows how one note is played on the piano."
Epigenetic activity is a previously unseen dimension of biology that may enable clearer detection of disease, monitoring of progression and improved treatment, and may provide entirely new biomarkers of disease susceptibility. "The symphony has only just come into view," Dr. Mitsuya said. "We can hear it, but we need to learn how all the parts are being played."
 

Dr. Mitsuya is a member of the Center for Pregnancy and Newborn Research in the Department of Obstetrics and Gynecology, School of Medicine, at the UT Health Science Center San Antonio and is engaged in epigenetic studies of placental function.



Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of Texas Health Science Center at San Antonio.


Journal Reference:
    1.    T. Watanabe, S.-i. Tomizawa, K. Mitsuya, Y. Totoki, Y. Yamamoto, S. Kuramochi-Miyagawa, N. Iida, Y. Hoki, P. J. Murphy, A. Toyoda, K. Gotoh, H. Hiura, T. Arima, A. Fujiyama, T. Sado, T. Shibata, T. Nakano, H. Lin, K. Ichiyanagi, P. D. Soloway, H. Sasaki. Role for piRNAs and Noncoding RNA in de Novo DNA Methylation of the Imprinted Mouse Rasgrf1 Locus. Science, 2011; 332 (6031): 848 DOI: 10.1126/science.1203919