Why is epigenetics important

Mutations in the proteins that carry out these epigenetic modifications, he says, can completely change the characteristics of a cell and promote cancer. Calico cats, which are nearly always female, demonstrate a type of epigenetic inheritance called X-inactivation. The result is patches of fur that are different colors. Biologists have known for a long time that gene expression is different in different cell types.

What makes one cell look and act different from another is the particular set of genes that are turned on in that cell and the particular proteins that are made as a result. B cells of the immune system make antibodies, for example, while muscle cells make a motor protein called myosin. The textbook view of gene regulation is that proteins called transcription factors act as molecular switches, turning genes on or off by binding to DNA.

In cells, DNA blue is wrapped around proteins called histones green and decorated with chemical tags that affect which genes are turned on or off. In this view, chromatin is seen as mostly structural packaging, without much of an active role. But researchers now know that chromatin has a more consequential role to play in gene expression. Modifications to the histones in chromatin, for example, can shape what regions of the genome are open or closed, and in turn affect which genes are turned on or off.

Epigenetic therapies like the ones he and his colleagues are working on help cells to restore many of these bookmarks, allowing them to bring gene expression back under control and return to normal.

Unlike genetic mutations, epigenetic changes can be reversible. Yet the idea that experience can alter gene expression is really nothing new. In a study forthcoming in the April issue of EHP , Jirtle and his colleagues also induced these alterations through maternal ingestion of genistein, the major phytoestrogen in soy, at doses comparable to those a human might receive from a high-soy diet.

The methylation changes furthermore appeared to protect the mouse offspring against obesity in adulthood, although there are hints that genistein may also cause health problems, via additive or synergistic effects on DNA methylation, when it interacts with other substances such as folic acid. In the 6 June Journal of Biological Chemistry and the 23 November Journal of Neuroscience , Szyf and many of the same colleagues also demonstrated that giving the amino acid l -methionine to older pups could negate the benefits of high-quality maternal care received when they were younger.

Along with behavior, mental health may be affected by epigenetic changes, says Arturas Petronis, head of the Krembil Family Epigenetics Laboratory at the Centre for Addiction and Mental Health in Toronto. His lab is among the first in the world, and still one of only a few, to study links between epigenetics and psychiatry. He and his colleagues are conducting large-scale studies investigating links between schizophrenia and aberrant methylation, and he says understanding epigenetic mechanisms is one of the highest priorities in human disease biology research.

The past decade has also been productive in developing strong links between aberrant DNA methylation and aging, says Jean-Pierre Issa, a professor of medicine at The University of Texas M. Anderson Cancer Center. Some of the strongest, decade-old evidence shows progressive increases in DNA methylation in aging colon tissues, and more recent evidence links hypermethylation with atherosclerosis. Altered, age-related methylation has also been found in tissues in the stomach, esophagus, liver, kidney, and bladder, as well as the tissue types studied by Esteller.

The accumulated evidence indicates that many genes, diseases, and environmental substances are part of the epigenetics picture.

However, the evidence is still far too thin to form a basis for any overarching theories about which substances and which target genes are most likely to mediate adverse effects of the environment on diseases, says Melanie Ehrlich, a biochemistry professor at the Tulane University School of Medicine and Tulane Cancer Center who has been conducting research on the topic for more than two decades.

That sense of uncertainty generally leaves epigenetics out of the regulatory picture. But Preston says the agency already relies more on its improving understanding of mechanistic processes, including epigenetics, and there is a clear effort within the EPA to expand genomics efforts both within the agency and with others with whom the agency works. At the FDA, scientists are investigating many drugs that function through epigenetic mechanisms although as spokes-woman Christine Parker notes, the agency bases its approvals on results of clinical trials, not consideration of the mechanism by which a drug works.

One such drug, azacitidine, has been approved for use in the United States to treat myelodysplastic syndrome, a blood disease that can progress to leukemia. The drug turns on genes that had been shut off by methylation.

Ehrlich points out that azacitidine also has effects at the molecular level—such as inhibiting DNA replication and apoptosis—that may be part of its therapeutic benefits.

Despite the potentially huge role that epigenetics may play in human disease, investment in this area of study remains tiny compared to that devoted to traditional genetics work.

Several efforts to change that are under way. They may be joined soon by organizations in Germany and India, where scientists plan to work on chromosomes 21 and X, respectively, says Sanger senior investigator Stephan Beck. But comprehensively studying all the epigenetic and epigenomic factors related to a multitude of diseases and health conditions will take much more work.

Jones and Robert Martienssen addressed some of the complexities of a comprehensive, worldwide Human Epigenome Project in the 15 December issue of Cancer Research. Reporting on a June workshop convened by the American Association for Cancer Research, they concluded that, despite all the looming difficulties, such a project is essential, and the technology is sufficiently advanced to begin.

A group of researchers has already started the footwork to launch a U. Other efforts are gaining ground. This information exchange network includes members in the public and private sectors spread throughout ten Western European countries.

Their objectives are to coordinate research, provide mentors, and encourage dialogue via their website. If a high number of cancer genes are eventually scrutinized, the effort would be the equivalent of thousands of Human Genome Projects. The dozen or so recipients are expected to launch their projects by fall The NIEHS has also begun to integrate epigenomics projects into its research portfolio over the past five to six years.

Cancer , 4 2 , — Giuliani , C. Gluckman , P. Heijmans , B. Hernando-Herraez , I. Heyn , H. Hubisz , M. Ingram , C. Jones , P. Laland , K. Moalem , S. Samson , M. Sankaran , V. Slotkin , R. Soubry , A. Sripichai , O. Tobi , E. Wiesenfeld , S. Yehuda , R. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search.

Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Method of inheritance. Influences on the development of the human species. Influences on evolution of modern humans. Case studies. Vulnerabilities of epigenetics.

Author biography. The role of epigenetics in human evolution. Alexander Osborne Alexander Osborne. Oxford Academic. Revision received:. Select Format Select format. Permissions Icon Permissions. Abstract This review aims to highlight the key areas in which changes to the epigenome have played an important role in the evolution and development of our species.

Figure 1. Open in new tab Download slide. Figure 2. Preservation of epigenetic marks during mitosis. Figure 3. Epigenetic prevention of Sickle Cell Anaemia. Google Scholar Crossref. Search ADS. The Epigenetic side of human adaptation: hypotheses, evidences and theories.

Persistent Epigenetic differences associated with prenatal exposure to famine in humans. The interplay between DNA methylation and sequence divergence in recent human evolution. In contrast, methylation of a different lysine K4 on the same histone H3 is a marker for active genes Egger et al. RNA might affect gene expression by causing heterochromatin to form, or by triggering histone modifications and DNA methylation Egger et al.

Table 1 ATRX gene and hypomethylation of certain repeat and satellite sequences. Fragile X syndrome has symptoms that include chromosome instability and intellectual disabilities. ICF syndrome has symptoms that include chromosome instability and immunodeficiency. Its etiology involves deregulation of one or more imprinted genes at 15q11—13 maternal.

Prader—Willi syndrome has symptoms that include obesity and intellectual disabilities. Its etiology involves deregulation of one or more imprinted genes at 15q11—13 paternal. BWS is characterized by organ overgrowth. Its etiology involves deregulation of one or more imprinted genes at 11p Rett syndrome has symptoms that include intellectual disabilities. The symptom of alpha-thalassaemia one case is anemia.

Various cancers have different symptoms and etiologies. For instance, some cancers have symptoms that include microsatellite instability.

Their etiologies involve de novo methylation of the MLH1 gene. Some cancers have symptoms that include disruption of Rb and the p53 pathway, and uncontrolled proliferation. Their etiologies involve de novo methylation of various gene promoters. Their etiologies involve loss of imprinting. Leukemia has symptoms that include disturbed hematopoiesis. Rubinstein—Taybi syndrome has symptoms that include intellectual disabilities.

Its etiology involves mutation in CREB-binding protein histone acetylation. Coffin—Lowry syndrome has symptoms that include intellectual disabilities. Its etiology involves mutation in Rsk-2 histone phosphorylation. Disrupting any of the three systems that contribute to epigenetic alterations can cause abnormal activation or silencing of genes.

Such disruptions have been associated with cancer , syndromes involving chromosomal instabilities, and mental retardation Table 1. The first human disease to be linked to epigenetics was cancer, in Because methylated genes are typically turned off, loss of DNA methylation can cause abnormally high gene activation by altering the arrangement of chromatin. On the other hand, too much methylation can undo the work of protective tumor suppressor genes.

However, there are stretches of DNA near promoter regions that have higher concentrations of CpG sites known as CpG islands that are free of methylation in normal cells. These CpG islands become excessively methylated in cancer cells, thereby causing genes that should not be silenced to turn off. This abnormality is the trademark epigenetic change that occurs in tumors and happens early in the development of cancer Egger et al.

Hypermethylation of CpG islands can cause tumors by shutting off tumor-suppressor genes. In fact, these types of changes may be more common in human cancer than DNA sequence mutations Figure 2. Furthermore, although epigenetic changes do not alter the sequence of DNA, they can cause mutations. About half of the genes that cause familial or inherited forms of cancer are turned off by methylation. Hypermethylation can also lead to instability of microsatellites, which are repeated sequences of DNA.

Microsatellites are common in normal individuals, and they usually consist of repeats of the dinucleotide CA. Too much methylation of the promoter of the DNA repair gene MLH1 can make a microsatellite unstable and lengthen or shorten it Figure 2.

Fragile X syndrome is the most frequently inherited mental disability, particularly in males. Both sexes can be affected by this condition, but because males only have one X chromosome , one fragile X will impact them more severely. Indeed, fragile X syndrome occurs in approximately 1 in 4, males and 1 in 8, females. People with this syndrome have severe intellectual disabilities, delayed verbal development, and "autistic-like" behavior Penagarikano et al.

Fragile X syndrome gets its name from the way the part of the X chromosome that contains the gene abnormality looks under a microscope; it usually appears as if it is hanging by a thread and easily breakable Figure 3.

The syndrome is caused by an abnormality in the FMR1 fragile X mental retardation 1 gene. However, individuals with over repeats have a full mutation , and they usually show symptoms of the syndrome. This methylation turns the gene off, stopping the FMR1 gene from producing an important protein called fragile X mental retardation protein. Loss of this specific protein causes fragile X syndrome. Although a lot of attention has been given to the CGG expansion mutation as the cause of fragile X, the epigenetic change associated with FMR1 methylation is the real syndrome culprit.

Fragile X syndrome is not the only disorder associated with mental retardation that involves epigenetic changes. Because so many diseases, such as cancer, involve epigenetic changes, it seems reasonable to try to counteract these modifications with epigenetic treatments.

These changes seem an ideal target because they are by nature reversible, unlike DNA sequence mutations. The most popular of these treatments aim to alter either DNA methylation or histone acetylation.