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Feb 1, 2009 (Vol. 29, No. 3)

Epigenomics Rises as Key Research Tool

Emerging Approach Offers Additional Avenue to Better Understand Mechanisms of Disease

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    The mother of the mouse on the left received a normal diet, while the mother of the mouse on the right received a diet supplemented with methyl donors such as choline, betaine, folic acid, and vitamin B12.

    The nature-nurture relationship has attracted fascination throughout history. Roman mythology tells us that in 753 B.C. Romulus slew his twin brother Remus, in a fight over who would become king of the city known today as Rome—and this is far from being the only example of dissimilar phenotypes despite close genetic resemblance.

    Modern medicine revealed that even monozygotic twins are discordant for many conditions and characteristics such as diabetes, schizophrenia, major depression, alcoholism, and body weight. In addition, the first report of monozygotic twins who developed Huntington’s disease over seven years apart, despite harboring the same number of genomic CAG repeats, was recently published.

    It is increasingly evident that genetics  alone cannot explain the complexity of phenotypes in the living world. Heritable phenotypic characteristics that are not caused by DNA sequence alterations represent the object of epigenetics and include potentially reversible changes such as histone modifications, DNA methylation, and imprinting. At the interface between epigenetics and genomics, a new discipline that is emerging, epigenomics, promises to profoundly change the way we envision phenomena in the biological and medical sciences.

    In an elegant experiment, Randy L. Jirtle, Ph.D., professor of radiation oncology and director of the epigenetics and imprinting laboratory at Duke University, demonstrated how events from early development influence the phenotype by modifying the epigenome.

    Two inbred mice, despite being genetically identical and having the same sex and age, were found to be phenotypically distinct. While the mother of one of the mice received a normal diet, the other mother’s diet was supplemented with methyl donors such as choline, betaine, folic acid and vitamin B12. Since the mice were genetically identical, phenotypic differences were the result of epigenetic, as opposed to genetic changes and the investigators demonstrated that in the brown offspring, specific DNA regions became hypermethylated.

    Animal models have guided fundamental questions relevant for human biology. Particularly while exploring the epigenome, however, it is important to remember and appreciate the differences between species. As Dr. Jirtle points out, “mice are not humans; there are big differences between their epigenomes.” Genetic imprinting, in which either the maternal or the paternal copy of a specific gene is silenced, provides a relevant example.

    The overlap between the repertoires of imprinted genes between mice and humans is estimated to be only about 30%. Relevant examples are provided by the HOX genes, of which 23% are predicted to be imprinted in humans but not in mice. On the other hand, the Igf2r tumor suppressor gene is imprinted in mice, whereas it is expressed from both parental copies in humans. Thus, evidence indicates that imprinting plays a disproportionately important role in disease formation that is species dependent.

    Consequently, ongoing efforts in the Jirtle lab are channeled toward mapping all human-imprinted genes and their ensemble of imprint regulatory elements:  the imprintome. One region of interest, on chromosome 22, contains imprinted genes that map into a genomic region associated with the maternal inheritance of schizophrenia. Interestingly, the same genomic region in mice contains no imprinted genes.

    The newly identified imprinted potassium channel gene KCNK9 is frequently amplified in breast cancer; however, it is unknown whether overexpression can also occur through loss of imprinting.  “I honestly do not believe we can fully understand cancer without identifying the imprinted genes in humans and determining how they are epigenetically regulated,” says Dr. Jirtle. “This is the information that is absolutely required to improve our ability to diagnose, prevent, and treat human diseases and neurological disorders.”

    Although recent years revolutionized our understanding of the human genome, the mechanisms that different cell types employ under different circumstances to perform their genetic program still remains a mystery—yet these mechanisms hold the key to the essence of life.

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