Epigenetics PDF

Epigenetics What is epigenetics? Epigenetics is the study of how behavior and environment can cause changes that affect the way genes work. Unlike genetic changes, epigenetic changes are reversible and do not change the DNA sequence, but they can change how the body reads a DNA sequence...

Epigenetics What is epigenetics? Epigenetics is the study of how behavior and environment can cause changes that affect the way genes work. Unlike genetic changes, epigenetic changes are reversible and do not change the DNA sequence, but they can change how the body reads a DNA sequence. While genetic changes can alter which protein is made, epigenetic changes affect gene expression to turn genes “on” and “off.” Today, there is some level of evidence linking a wide variety of illnesses including cancers of almost all types, respiratory, cardiovascular, reproductive, and autoimmune diseases, cognitive dysfunction, behavior and neurobehavioral illnesses, and other health indicators with epigenetic mechanisms. Types of epigenetic processes: Chemical changes - include methylation, acetylation, phosphorylation, ubiquitylation, and sumolyation Chromatin modification - alters chromatin structure to influence gene expression. Chromatin can be modified by substances such as acetyl groups (acetylation), enzymes, and others. Non-coding RNA - helps control gene expression by attaching to coding RNA, along with certain proteins, to break down the coding RNA so that it cannot be used to make proteins. Non-coding RNA may also recruit proteins to modify histones to turn genes “on” or “off.” Known or suspected drivers behind epigenetic processes include many agents, including heavy metals, pesticides, diesel exhaust, tobacco smoke, polycyclic aromatic hydrocarbons, radioactivity, viruses, bacteria, hormones and basic nutrients. DNA methylation DNA methylation works by adding a methyl group (CH3) to DNA, predominantly where cytosine bases occur consecutively. The methyl group can be removed by a process called demethylation. Typically, methylation turns genes “off” and demethylation turns genes “on.” Role of DNA methylation in gene expression during early development: X-chromosome inactivation X-chromosome inactivation (XCI) is the form of dosage compensation in mammalian female cells to balance X-linked gene expression levels of the two sexes.  Xist gene appears to be involved in "choosing“ which X chromosome is inactivated. Once Xist initiates the inactivation of an X chromosome, the silencing of that chromosome is maintained in at least two ways: Methylation - the Xist locus on the active X chromosome becomes methylated, while the active Xist gene (on the inactive X chromosome) remains unmethylated Conversely, the promoter regions of numerous genes are methylated on the inactive X chromosome and unmethylated on the active X chromosome Histone modification DNA wraps around proteins called histones. When histones are tightly packed together, the gene is turned “off.” When histones are loosely packed, more DNA is exposed and accessible so the gene is turned “on.” Chemical groups can be added or removed from histones to make the histones more tightly or loosely packed, turning genes “off” or “on.” Non-coding RNAs Non-coding RNA helps control gene expression by attaching to coding RNA, along with certain proteins, to break down the coding RNA so that it cannot be used to make proteins. Non-coding RNA may also recruit proteins to modify histones to turn genes “on” or “off.” Epigenetics and development Epigenetic changes begin before birth. All cells regardless of type and function, have the same genome. Epigenetics helps determine the fate of cells during differentiation. Epigenetics and age Epigenetics/epigenome changes throughout your life. Not the same at birth as during childhood or adulthood. EXAMPLE: STUDY OF NEWBORN VS. 26-YEAR-OLD VS. 103-YEAR-OLD DNA methylation at millions of sites were measured in a newborn, 26- year-old, and 103-year-old. The level of DNA methylation decreases with age: highest in newborns, intermediate in 26-year olds and lowest in the 103-year-old group. Epigenetics and reversibility Not all epigenetic changes are permanent. Some epigenetic changes can be added or removed in response to changes in behavior or environment. Ex: smokers vs non-smokers vs former smokers Smoking can result in epigenetic changes. For example, at certain parts of the AHRR gene, smokers tend to have less DNA methylation than non-smokers. The difference is greater for heavy smokers and long-term smokers. After quitting smoking, former smokers can begin to have increased DNA methylation at this gene. Eventually, they can reach levels similar to those of non- smokers. In some cases, this can happen in under a year, but the length of time depends on how long and how much someone smoked before quitting. Epigenetics and health Infections Infections can change the epigenetics to weaken the immune system, helping the infection to thrive and progress. Example: Mycobacterium tuberculosis infections can cause changes to histones in some of the immune cells that result in turning “off” the IL-12B gene. Down regulation of the IL- 12B gene weakens the immune system and improves the survival of Mycobacterium tuberculosis. Epigenetics and health Cancers Some epigenetic changes increase the risk of cancer. Example: a mutation in the BRCA1 gene increases the risk for breast and other cancers. Similarly, increased DNA methylation that results in decreased BRCA1 gene expression raises the risk for breast and other cancers. While cancer cells have increased DNA methylation at certain genes, overall DNA methylation levels are lower in cancer cells compared with normal cells. Different types of cancer that look alike can have different DNA methylation patterns. Epigenetics can be used to help determine which type of cancer a person has or can help to find hard to detect cancers earlier. Epigenetics alone cannot diagnose cancer. Example: Colorectal cancers have abnormal methylation at DNA regions near certain genes, which affects expression of these genes. Some commercial colorectal cancer screening tests use stool samples to look for abnormal DNA methylation levels at one or more of these DNA regions. It is important to know that if the test result is positive or abnormal, a colonoscopy test is needed to complete the screening process. Nutrition during pregnancy A pregnant woman’s environment and behavior during pregnancy, such as whether she eats healthy food, can change the baby’s epigenetics. Some of these changes can remain for decades and might make the child more likely to get certain diseases. Example: Dutch winter famine (1944-1945) People whose mothers were pregnant with them during the famine were more likely to develop certain diseases such as heart disease, schizophrenia, and type 2 diabetes. About 60 years after the famine, researchers looked at methylation levels in people whose mothers were pregnant with them during the famine and recorded increased methylation at some genes and decreased methylation at other genes compared with their siblings who were not exposed to famine before their birth. These differences in methylation could help explain why these people had an increased likelihood for certain diseases later in life. Epigenetics and twin studies 40 pairs of identical twins, ranging in age from 3 to 74 Younger twin pairs and those who shared similar lifestyles and spent more years together had very similar DNA methylation and histone acetylation patterns. Older twins, especially those who had different lifestyles and had spent fewer years together, had much different patterns in different tissues (lymphocytes, epithelial mouth cells, intra-abdominal fat, some muscles). 4x as many differentially expressed genes between a pair of 50-year-old twins compared to 3-year-old twins, and the 50-year-old twin with more DNA hypomethylation and histone hyperacetylation (the epigenetic changes usually associated with transcriptional activity) had the higher number of overexpressed genes. The degree of epigenetic change was directly linked with the degree of change in genetic function. Genome vs epigenome Epigenome - the multitude of chemical compounds that can tell the genome what to do. Genome - the complete set of DNA that is unique to the individual.