31:190 Spring 2012 Lecture 3 Introductions to: DNA methylation and its impact on gene regulation Intestinal Flora and Leaky Gut Syndrome

What is Epigenetics ? Greek, epi = above, upon - genetics The study of heritable changes in gene function that occur without a change in the DNA sequence. the study of changes in gene silencing or activation that occur without changes in the genes themselves. Many genes in the body are permanently turned off as part of normal development. But sometimes that process goes awry, turning off genes that should otherwise remain active.... These changes can be brought about by environment, past experience, or even personal perceptions. the science concerned with the analysis of development. In biology, while the subject of genetics focuses on how organisms can inherit traits by inheriting genes from their parent(s), which encode information for cell function as sequences of DNA, epigenetics is sometimes used to refer to additional methods of biological inheritance that determine how the DNA pattern is used.

What is epigenetics? Epigenetics literally "on" genes refers to all modifications to genes other than changes in the DNA sequence itself. Epigenetic modifications include addition of molecules, like methyl groups, to the DNA backbone. Adding these these groups changes the appearance and structure of DNA altering how a groups changes the appearance and structure of DNA, altering how a gene can interact with important interpreting (transcribing) molecules in the cell's nucleus. How do epigenetic modifications affect genes? Genes carry the blueprints to make proteins in the cell. The DNA sequence of a gene is transcribed into RNA, which is then translated into the a gene is transcribed into RNA, which is then translated into the sequence of a protein. Every cell in the body has the same genetic information; what makes cells, tissues and organs different is that different sets of genes are turned on or expressed.

What is Epigenetics ? Our working definition for the lecture Study of phenomenon EPI Not DNA Sequence Effect Gene function Heritable

A bit of history DNA is the same in all cells of an organism DNA modification... DNA methylation Protein modification... Chromatin, Histones

Figure 1.8a Genomes 3 (© Garland Science 2007)

Figure 1.4b Genomes 3 (© Garland Science 2007) RNA

... In packaging DNA to better fit into a confined space, a problem develops, much as when one packs too many books onto library shelves: It becomes harder to find and read the book of choice, and thus an indexing system is needed. Chromatin, as genome indexing platform, provides this indexing

Patterns of DNA methylation and topology of chromatin structure -> more than 3100 references afterwards Paper has been cited 786 (WoK)

Epigenetics is everywhere And Epigenetics has always been all the weird and wonderful things that cannot be explained by genetics You can inherit something beyond the DNA sequence. Thats where the real excitement in genetics is now (2003)

What are the interesting research questions (... For psychologists) concerning of DNA methylation?

Familiar nutrients like folic acid, B vitamins and SAM-e (S-Adenosyl methionine, a popular over-the-counter supplement) are key components of this methyl-making pathway. Diets high in these methyl-donating nutrients can rapidly alter gene expression, especially during early development when the epigenome is first being established.

Diet During Early Development Can Cause Changes Lasting Into Adulthood Your mother's diet during pregnancy and what you're fed as an infant can cause critical changes that stick with you into adulthood. Animal studies have shown that deficiency of methyl- donating folate or choline during late fetal or early postnatal development causes certain regions of the genome to be under-methylated for life. For adults, a methyl deficient diet still leads to a decrease in DNA methylation, but the changes are reversible with resumption of a normal diet.

Toxins and Supplements Chemicals and additives that enter our bodies can also affect the epigenome. Bisphenol A (BPA) is a compound used to make polycarbonate plastic. It is in many consumer products including water bottles and tin cans. When controversial reports questioning the safety of BPA came out in 2008, some merchants ceased to carry products made with BPA. When pregnant yellow agouti mothers were fed BPA, more yellow, unhealthy babies were born than normal. Exposure to BPA during early development had caused decreased methylation of the agouti gene. However, when BPA-exposed, pregnant yellow mice were fed methyl-rich foods, the offspring were predominantly brown. The maternal nutrient supplementation had counteracted the negative effects of exposure.

A Bee's Royal Diet Royal jelly is a complex, protein-rich substance secreted from glands on the heads of worker bees. A larva destined to become a queen is fed large quantities of royal jelly inside a specially constructed compartment called a queen cup. The larvae that develop into workers and queens are genetically identical. But as a result of the royal jelly diet, the queen will develop functional ovaries and a larger abdomen for egg laying, while worker bees remain sterile. She'll also develop the necessary behaviors to act as queen, such as killing rival queens, making communication sounds known as "piping," and going on "mating flights." The queen is fed royal honey exclusively for the rest of her life. In a recent series of experiments, scientists determined that royal jelly silences a key gene (Dnmt3), which codes for an enzyme involved in genome-wide gene silencing. When Dnmt3 is active in bee larvae, the queen genes are epigenetically silenced and the larvae develop into the default "worker" variety. But when royal jelly turns Dnmt3 off, certain genes jump into action that turn the lucky larvae into queens.

Don't Count Dad Out So if a pregnant mother's diet can affect the child's epigenetic outcome, can dad's diet do the same? Quite possibly, according to scientists who delved into the well-kept, historical records of annual harvests from a small Swedish community. These records showed that food availability between the ages of nine and twelve for the paternal grandfather affected the lifespan of his grandchildren. But not in the way you might think. Shortage of food for the grandfather was associated with extended lifespan of his grandchildren. Food abundance, on the other hand, was associated with a greatly shortened lifespan of the grandchildren. Early death was the result of either diabetes or heart disease. Could it be that during this critical period of development for the grandfather, epigenetic mechanisms are "capturing" nutritional information about the environment to pass on to the next generation? Food abundance for the grandfather was associated with a reduced lifespan for his grandchildren.

-Beneficial bacteria take part in our digestion and absorption of our food -Gut bacteria produce a number of enzymes that break down proteins, carbohydrates, fiber and fats. -Gut bacteria produce various substances that transport vitamins, minerals and other nutrients from our food that we eat through the gut wall that is then absorbed into our blood stream to nourish our body. -Some nutrients are short lived in the body so for this reason gut bacteria can actively synthesize a number of nutrients that are essential for us: vitamin k2 (menaquinone), B1, B2, B3, B6, B12, folic acid, pantothenic acid and some amino acids. - So without a good healthy gut flora your body will be deficient in nutrients, they will simply not be made or absorbed properly. Intestinal Flora or Gut Bacteria

Essential or beneficial flora -These bacteria are referred to as our indigenous friendly bacteria. The main members of this group are: Bifidobacteria (Bifidobacterium bifidum), Lactobacteria (Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus rhamnosus), Propionobacteria, Peptostreptococci and Enterococci. -Beneficial flora is made up of beneficial or good bacteria also called probiotic which are housekeepers of the gut, without them your gut cannot be healthy. -In a healthy body these beneficial bacteria predominate and control all other microbes. - The beneficial bacteria provide a natural barrier and protects us against all sorts of invaders, bacteria, parasites, fungi, viruses, toxins etc. that are in our food and drink that we ingest every day. Apart from providing us with a physical barrier the beneficial bacteria produce antibiotic like substances that are antifungal and antiviral that dissolve viruses and 'bad' bacteria. They also reduce pH near the wall of the gut making it uninhabitable for the 'bad' bacteria to colonize.

How Beneficial Gut Bacteria Can Be Damaged or Reduced -Antibiotics and penicillin can have a devastating affect on beneficial bacteria not only in the gut but in other organs and tissues as well. -It takes between 4 to 8 weeks depending on the species of beneficial bacteria to re-establish in the gut. This gives a window of opportunity for the bad bacteria, the disease causing bacteria, viruses and fungi to establish themselves on the gut wall. -The contraception pill, prolonged stress, dentistry work and exposure to toxic substances also can damage our friendly bacteria. -Diet of course has a large impact on the gut flora. -Convenient processed foods effects the gut flora. -Drinking milk and eating meat from animals that are routinely given antibiotics, steroids and other drugs can damage the gut flora. -Too much sugar foods and processed carbohydrates increase the number and create a habitat for a number of different fungi.

Beneficial Gut Flora and Immune System Health -Approximately 83% of our immunity is located in the gut wall. - A large percentage of diseases can be traced back to a damaged or an abnormal gut flora. -The gut flora keeps two arms in the immune system in balance and encourages the immune system to respond appropriately to 'bad' microbes. The first arm say is responsible for what we are exposed to in our environment. When the gut flora is damaged, the microbes (the 'bad' bacteria) are able to break through the gut wall, it becomes what is known as leaky gut syndrome. The immune system becomes less efficient and starts letting in unwanted microbes and toxins through the gut wall. The second arm of your immune system will try and compensate for the first arm and will become hyperactive. -The second arm of your immune system is responsible for allergic type reactions. It is also the root cause of autoimmune diseases. The most common examples include: Celiac disease, Multiple sclerosis (MS), Graves' disease, Rheumatoid arthritis (RA) and so on.