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Epigenetics: No single factor determines its role in the deveopment of a multicellular organism

Epigenetics: No single factor determines its role in the deveopment of a multicellular organism

Thinking that the article by Heidi Chial, Ph.D. and Jef Akst, on ‘Epigenetics‘ published in the Nature weekly magazine would interest GNOBB readers. The same informative article is being posted again. The Coordinator invites opinion from GNOBB readers to shed light on this complex genetic phenomenon. which puzzles geneticists for a long time as to why individuals with the same genotype develop differently, the striking example being honeybee. In the Queen honeybee its food habit is reported to play a very important role in its abnormally large body size and shape.

In 2010, a group of researchers at the Stanford University School of Medicine in California uncovered a set of three mutations in the microscopic roundworm Caenorhabditis elegans, each capable of extending the life span of the worms by up to 30%. This exciting discovery prompted the research team to ask whether descendants of these worms could live longer, even if they didn’t inherit the original mutation from their parents. Much to the researchers’ surprise, the descendants lacking the original mutation continued to exhibit longer life spans for up to three generations. How could this happen? Recently it it has been shown epigenetic changes are linked to a wide range of complex human diseases, including blood cancers, tumors, autism, and autoimmune diseases.Remarkably, epigenetic changes to DNA are branded into the genome in a manner that can sometimes be inherited by future generations. What, then, are these traces — these brands that somehow stick to the lineages of organisms?

Transgenerational longevity in the roundworm is just one example among many epigenetic phenomena — differences in the traits of organisms (their phenotypes) that occur without any accompanying changes or mutations in genomic DNA sequences (their genotypes). Epigenetic events have both intrigued and puzzled researchers over the years. How is it that two organisms with identical genotypes can sometimes exhibit strikingly different phenotypes?

In the 1980s, researchers discovered that the answer to this question is centered on specific chemical modifications that occur on the genomic DNA and its associated histone proteins, without changing the identity of the base pairs that make up the DNA. What are these modifications, and how do they affect phenotypes? Introductory biology teaches us that DNA is built from four different nucleotides: adenine, cytosine, guanine, and thymine. In epigenetic modification, a methyl group (–CH3) is added to specific cytosine bases of the DNA. This enzymatic process, called DNA methylation, is known to play a key role in both development and disease. Methylation is a physical modification to the DNA that affects the way the molecule is shaped and, consequently, regulates which genes are transcriptionally active.

Recently, another type of epigenetic modification of DNA was discovered: the addition of a hydroxymethyl group (–CH2–OH) to specific cytosine bases of DNA. In eukaryotic cells, genomic DNA is wrapped around histone proteins to form nucleosomes, which together form chromatin fibers that can be further compacted into dense coils. Histone proteins can also be modified in a number of ways; in addition to methylation, they can be modified with acetyl groups (acetylation), phosphate groups (phosphorylation), ubiquitin proteins (ubiquitylation), and SUMO proteins (sumoylation). Epigenetic modifications to histone proteins can either inhibit or promote coiling or condensation of the chromatin. Collectively, these epigenetic modifications to DNA molecules and histones lead to changes in chromatin organization, which in turn affect how the associated genes are expressed, ultimately influencing an organism’s physiology and behavior.

But epigenetic phenomena are not restricted to DNA methylation and various types of histone modifications. In an ever-expanding field of research, scientists have found that RNA molecules themselves can also regulate DNA directly by physically blocking or influencing the reading of DNA sequences. These RNA molecules aren’t the classic messenger RNA (mRNA) molecules we learn about in introductory biology that carry the information from DNA in the nucleus to the cytoplasm of a cell. Rather, these RNA molecules — called antisense RNAs, microRNAs, and noncoding RNAs — stay primarily within the nucleus, where they induce changes in DNA function. How do these RNA molecules work? While scientists are not entirely sure, recent discoveries show that these RNAs likely bind to histone proteins or help repress transcription of gene promoters.

Can environmental factors cause epigenetic modifications to DNA? It turns out they can, and in extraordinary ways. A honeybee colony provides a striking example of epigenetic variation and the interplay between genomes and the environment. Although identical in genetic sequence, queen bees and worker bees are entirely different in terms of their behavior, physiology, and appearance; phenotypic differences between queen bees and worker bees abound. For example, queen bees can produce as many as 2,000 eggs in a single day, whereas worker bees are sterile. Worker bees spend their days foraging for food, collecting pollen, maintaining the hive, and fighting off invaders, while queen bees spend their days having food delivered to them and laying eggs to keep the hive populated with enough workers. Queen bees are 5 times larger than worker bees. Not surprisingly, the life span of queen bees is typically 20 times longer than that of worker bees.

What is responsible for these dramatic differences? In this case, the phrase “you are what you eat” comes to mind. Both queen and worker bee larvae are initially fed a diet of royal jelly, which is provided by nurse bees. However, the worker bee larvae are rapidly weaned and fed a diet of nectar and pollen. In stark contrast, the queen bees are bathed in royal jelly throughout larval development, and they continue to feast on the royal-jelly diet as adults. What is so special about royal jelly? Recent research has shown that the ingredients in royal jelly are capable of inhibiting an enzyme called cytosine methyltransferase that methylates cytosine bases in honeybee DNA. Indeed, by simply lowering the expression levels of this enzyme in recently hatched honeybee larvae, researchers have mimicked the effects of royal jelly, causing larvae initially destined to become worker bees to exhibit characteristics of queen bees. By comparing the levels of cytosine methylation and gene expression across the genome in queen bees versus worker bees, researchers have also identified potential target genes whose expression is higher in queen bees (presumably because of royal jelly-mediated decreases in methylation) compared to worker bees, which could explain the differences between the two castes.

While form and function are clearly not as strictly dictated by epigenetic phenomena in humans as they are in honeybees, researchers increasingly recognize a role for epigenetics in human growth, development, and disease. Remarkably, targets of epigenetic modification can range from large segments of chromosomes to individual genes. During mammalian development, for example, epigenetic mechanisms are responsible for inactivating one of the two copies of the X chromosome in females. Tortoiseshell cats provide one of the most visually striking examples of X chromosome inactivation, which is responsible for their motley coat patterns.

Genetic imprinting, on the other hand, relies on epigenetic marks that result in the expression of only one copy of a specific gene: either the copy inherited from the mother or the copy inherited from the father. Notably, researchers have identified at least 80 imprinted genes in humans and mice. Many of these genes play a role in embryonic growth and development. Alterations in genetic imprinting are associated with diverse forms of human disease, including Prader-Willi syndrome, Angelman syndrome, Albright hereditary osteodystrophy (pseudohypoparathyroidism type 1a), and Beckwith-Wiedemann syndrome. Other forms of human disease are linked to mutations in genes that themselves regulate epigenetic changes across the genome, such as Rett syndrome; immunodeficiency, centromeric region instability, and facial anomalies (ICF) syndrome; alpha-thalassemia mental retardation syndrome; X-linked syndrome; and Rubinstein-Taybi syndrome.

It is important to keep in mind that alterations in epigenetic modifications are not always associated with aberrant development or disease; rather, organisms with identical genotypes can show different phenotypes, depending on their life experience. Studies of human twins, for example, have shown remarkable differences among identical twins that likely stem from different epigenetic signatures in their DNA, presumably accumulated over the course of each twin’s life.

In the past 50 years, our growing understanding of epigenetics and its importance in development and disease has transformed how we think about the role of nature versus nurture. Clearly, epigenetic mechanisms are not strictly dictated by either of these two influences, and they have helped us reform our views regarding the role of nature versus nurture. With that understanding, scientists are realizing that epigenetic modifications have a powerful hand in the lives of organisms, as well as in the evolution of species. Indeed, without altering the identity of the DNA base pairs themselves, epigenetic modifications can shape many aspects of an organism’s phenotype.

Today, widely available “epigenomic” techniques allow researchers to probe for epigenetic change

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