Thursday, September 11, 2014

Review of Epigenetic Influences Offers New Perspectives on Health and Illness

Human lives are governed by vanishingly small threads of chemical instructions, bundled into orderly parcels and locked deep within the heart of our cells. These filaments are DNA, a kind of molecular textbook that uses short sequences called genes to tell the body what proteins to make and how to use them. Genes give rise to all sorts of attributes, including what we look like, our personalities, and our health. But these genes are not set in stone. Epigenetics is a branch of science dedicated to understanding the ways that our genes are influenced by factors other than DNA, such as drugs, foods, behaviors, and life experiences.

An individual's so-called "epigenome" exerts vast and enduring control throughout his or her life, from conception to death and even beyond. Emerging research suggests that epigenetic effects also play a powerful role in the development of disease, revealing increasingly refined targets for future scientific and biomedical studies. This week, a trio of scientists from Howard University released an extensive review that details these effects. Their paper, published in Frontiers in Cell and Developmental Biology, offers a convincing argument for increased epigenetic research and better public understanding. Ultimately, they contend, mastery of epigenetics will lead to improved well-being and longer, healthier lives.

First, a bit of background. If DNA is the textbook, promoter regions are the subject headings that tell its readers, proteins called transcription factors, where to begin. Transcription factors encourage a copying enzyme called RNA polymerase to re-write every word of the DNA molecule on a new template, a strand of material called messenger RNA. This new molecule is not actually identical in sequence to the parent DNA strand; instead, it is made up of opposite and complementary "words," or codons. A sequence of related codons on a strand of DNA is called a gene.

Each codon is comprised of three small bags of chemicals called nucleotides. Nucleotides are extremely picky characters and will only bind in concrete twosomes: C with G, and A with T or U. The sequence of nucleotides created by RNA polymerase depends on the order of codons presented by the parent strand of DNA. That is, if the DNA textbook reads CTG, RNA polymerase will re-write this codon as GAC. The strand of messenger RNA that results from all this copying will ultimately create a blueprint of the organism's genome from which cellular factories can build proteins, the workhorses of the body.

Epigenetic influences can greatly impact this copying process. By tagging key segments of DNA with chemical markers, the epigenome can enhance, prevent, or modulate local transcription, effectively controlling gene expression. This process can occur directly, in the case of a drug that interacts biochemically with a gene, or indirectly, when a signal cascade triggered by the environment leads to the release of molecules that prompt an epigenetic response. Through complex processes called methylation, histone modification, and RNA-mediated silencing, the epigenome can exert a surprisingly powerful force on the body, starting at the very beginning of life.

Early in development, a rapid round of demethylation and remethylation "resets" the fetal genome and erases potentially harmful changes that have accumulated in parental DNA. Even so, a mother's environment during pregnancy readily impacts the genome of her child. For instance, women whose diets vary with the seasons develop an epigenome that regulates their nutritional requirements in accordance with the environment. Those who are pregnant during especially lean months tend to have low birth weight babies who remain smaller throughout life than those who were born of more plentiful times. Maternal stress during pregnancy also has epigenetic effects on the fetus, ultimately increasing the child's susceptibility to neurological disease and heightening his or her stress response. These kinds of diet and stress-mediated markers can become imprinted upon the child's DNA, later going on to evade the genetic reboot and influence future generations.

An infant's epigenome is exquisitely sensitive to the presence or absence of bonding and attachment behaviors soon after birth. Baby mice who are routinely groomed by their mothers exhibit a much healthier levels of stress and anxiety later in life than those who were ignored. Like human children, mice who are left to fend for themselves as babies appear to develop key epigenetic signatures in genes that control cortisol receptors, those areas of the brain that regulate the fight-or-flight response.  These same changes occur in children who witness violence or experience abuse, predisposing them to developing mood disorders as adults.

Epigenetic modifications also result from our own individual choices, both positive and negative. For instance, research suggests that healthy decisions regarding diet and exercise actually prevent disease on a molecular level. The high levels of folic acid and antioxidants found in fresh fruits and vegetables work to reduce DNA damage by cleaning up regions that have been inappropriately silenced or activated. Alternative medicine modalities such as acupuncture have also been lauded for their beneficial genetic effect on cardiac health. Similarly, exercise prompts activation of genes that increase metabolism and strengthen muscles, even in otherwise sedentary individuals.

Drugs, alcohol, and environmental toxins also induce epigenetic changes, but they are far less favorable. Instead, these substances often modify DNA in ways that encourage proliferation of rogue tumor cells or alter the genes that control neurotransmitter release. Some studies also indicate that altered circadian rhythms could be driving epigenetic modifications that underlie the current epidemic of obesity and type 2 diabetes. Unsurprisingly, many diseases have been shown to result from unsavory changes in the epigenome, such as Alzheimer's, arthritis, heart disease, and cancer.

In recent years, biologists have uncovered a surprising and significant link between our nuclear microcosm and the external environment. For example, intensely stressful events such as famine and abuse imprint genes that will go on to affect future descendants; nutrients found in herbs and spices protect the DNA from harmful mutations; and cancer cells derive potency from the silencing of their peers' tumor suppressor genes. Each of these discoveries implicates the study of epigenetics as a central theme in human health and well-being, placing it at the heart of the burgeoning field of personalized medicine. A more comprehensive understanding of our plastic genome should allow doctors and individuals alike to make better decisions about the prevention and treatment of disease. Ultimately epigenetics seems to reveal that - for better or for worse - much of our health is truly in our own hands.

No comments:

Post a Comment