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Apr 1, 2013 (Vol. 33, No. 7)

Epigenetics Opens New Avenues for DNA Research

  • Social Environment Impact on Gene Expression

    Studies showing that the social environment influences gene expression by epigenetic modifications are unveiling a fascinating link between social adversity and pathology in later life. As part of these studies, it is relevant to remember that, in an animal model, licking and grooming were linked to CpG methylation changes in the hypothalamic glucocorticoid receptor of newborn pups, establishing causality between maternal care and the stress response in the offspring later in life.

    Moreover, adversity during childhood was shown to leave an epigenetic imprint that changes gene expression in very specific regions of the brain. The involvement of epigenetic changes in synaptic plasticity, cognitive processes, and the formation of long-term memories, and the epigenetic modulation of post-traumatic stress disorder, are emerging topics that promise to fathom some of the most challenging areas in biology.

  • Fetal Origins of Adult Disease Hypothesis

    While epigenetic changes may occur throughout life, embryogenesis is thought to be the period with the highest vulnerability. Epigenetics is providing a missing link to understand the ability of adverse conditions, acting during intrauterine development, to shape the risk of adult-onset diseases that clinically start decades later.

    This relationship, known as the fetal origins of adult disease hypothesis, or the Barker hypothesis, was first published in 1992 and subsequently confirmed epidemiologically for several health conditions. Studies on women prenatally exposed to famine during the Dutch Hunger Winter at the end of World War II revealed that nutritional deprivation, when occurring at critical intrauterine developmental stages, may cause epigenetic changes that shape the risk of specific adult-onset diseases in the fetus.

    Timing appears to be crucial, because exposure during critical windows of development was associated with specific disorders later in life. Recent years revealed that other types of exposures during intrauterine development, including nutritional compounds, maternal cigarette smoking, environmental polycyclic aromatic hydrocarbons, and endocrine-disrupting chemicals, may cause epigenetic changes in the fetus.

    These changes include aberrant DNA methylation, histone post-translational modifications, and microRNA dysregulation, and shape disease risk later in life.

    The possibility to transmit epigenetic modifications across several generations, a phenomenon known as transgenerational epigenetic inheritance, is emerging from animal and human studies. Vinclozolin, a fungicide used in the wine industry, whose two major metabolites are anti-androgenic compounds, was shown, in an animal model, to act at the time of embryonic sex determination and cause epigenetic modifications in the male germ cell line.

    These inherited modifications, occurring at multiple locations throughout the sperm epigenome, increased the risk of diseases for at least three generations after the initial exposure. Evidence is also accumulating for the ability of diethylstilbestrol, a nongenotoxic synthetic estrogen that decades ago was prescribed to prevent miscarriages, to cause transgenerational epigenetic effects.

    Animal studies revealed that this compound alters DNA methylation, and the increased susceptibility for adverse health effects appears to be transmitted across several generations though the maternal and, as some studies reveal, paternal germ cell lineage, and human studies showing transgenerational inheritance are attracting considerable attention.

  • Potential Reversibility

    The potential reversibility of epigenetic modifications, along with additional aspects, such as the recent finding that oncogene addiction extends to certain microRNA molecules, are opening new therapeutic perspectives. Four epigenetic targets, two DNA methyltransferase inhibitors and two histone deacetylase inhibitors, were approved in recent years by the FDA, and several other compounds are at various stages of preclinical and clinical development.

    One of the challenges that these therapeutic targets present is that they may change epigenetic marks on multiple genes, not all of them involved in pathogenesis. More specific drug targets, known as second-generation epigenetic compounds, are currently at various stages of preclinical and clinical development.

    Some of these, such as the small molecule inhibitors of the BET family bromodomains, or long noncoding RNA molecules that modulate gene expression, promise to much more selectively target the epigenetic dysregulation of specific genes.

    In addition, epigenetic biomarkers that visualize and monitor epigenetic changes at the molecular level, sometimes years before histological changes become apparent, emerge as a major practical application. These changes, which can be used for early detection and in prognostic, risk stratification, and therapeutic decisions, found an exciting place in the drug discovery pipeline.

  • The Road Ahead

    As a vibrant field, epigenetics promises much excitement and many surprises for years to come. While most research has focused on epigenetic changes within promoters and repetitive chromosomal regions, their occurrence within genes and intergenic regions is gaining considerable attention.

    Epigenome-wide association studies recently emerged as a new approach to study complex human diseases. Particularly given the dynamic nature of epigenetic marks, which change during development and differentiation, vary in a tissue-specific manner, and are reshaped in differentiated tissues over time, this approach presents multiple layers of challenges, but promises a wealth of information.

    Our knowledge about epigenetic crosstalk, the interplay among different layers of epigenetic modifications, is still in its infancy. The approximately 30 million CpG sites, the tens or hundreds of millions of histone tails from a haploid human genome that each can undergo various types of post-translational modifications, and the over 2,000 microRNAs discovered to date, forecast an epigenetic network with a complexity whose spectrum is far from being fathomable, even in the foreseeable future.

    As certain microRNAs may target tens to hundreds of gene products, and the same mRNA can be regulated by multiple micro-RNAs, and with microRNAs being estimated to regulate over 30% of the protein-coding genes, epigenetics develops into a more thought-provoking and intriguing area than we could ever have envisioned.

    Additionally, as recently pointed out, the bidirectional complex crosstalk between epigenetic and genetic changes has numerous far-reaching implications and should be more carefully scrutinized.


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