America’s biggest sporting event, Super Bowl Sunday, is an unofficial national holiday when friends, family, and occasionally strangers feast and gather in front of the television to watch two professional football teams battle for a championship. For days before and after, conversations in the classrooms or offices across the country would revolve around the match-up, the commercials, or the halftime show – and everyone, a football fan or not, would have an opinion. Often unmentioned, however, is the darker side of the festivity: concussions.
A concussion, also referred to as mild traumatic brain injury (MTBI) or minor head trauma, is a type of injury in which the brain function is altered due to a blow to the head or violent shaking of the head and upper body. Symptoms include, but are not limited to headaches, loss of appetite, mood change, nausea and amnesia. Concussions are especially common in contact-sport athletes, with football recording the greatest number of injuries (Daneshvar et al., 2011). For most people, concussion symptoms resolve themselves following rest, but some experience lingering effects and many face increased risk of repeat injury. In recent years, there is a growing awareness of the long-term impact of head trauma, no doubt due to high-profile suicide cases by former NFL stars such as Junior Seau, Dave Duerson and Jovan Belcher, all whom were diagnosed postmortem with chronic traumatic encephalopathy (CTE), a neurodegenerative disease linked to repetitive head trauma.
Much is still unknown about the mechanism mediating head trauma. However, studies have shown that individuals with G-219T TT polymorphism at the APOEε4 promoter have an increased risk for concussion (Terrell et al., 2008; Tierney et al., 2010). Interestingly, APOEε4, a key regulator of lipid metabolism, falls in the class of highly methylated CpG island promoter which is infrequently found in normal cells (Yu et al., 2013). Largely unmethylated, CpG islands refer to 500-bp regions that have GC frequency of more than 50% and observed/expected CpG ratio of 0.65 (Takai and Jones, 2002). The varying levels of APOEε4 methylation have been associated with Alzheimer’s disease, another type of neurodegenerative disease, and thus, it is not inconceivable that APOEε4 may also play a role in concussion and CTE development.
Studies have previously detected gene expression and epigenetic changes in head trauma using various rat models (Griesbach et al., 2002; Zhang et al., 2007). In cases of pediatric head trauma, scientists have found a significant decrease in histone H3 acetylation and dimethylation in the hippocampus within 6 hours post-injury with no changes in the overall H3 protein expression (Gao et al., 2006). These posttranslational modifications to histone proteins are normally associated with gene activation and their reduction thus suggests alteration in gene expression whereby many genes become turned off.
Scientists in Germany separately detected global hypomethylation in the brains of dexamethasone-induced trauma which corresponded to the accumulation of activated microglia and macrophage population (Zhang et al., 2007). The change in global DNA methylation level was time dependent, but unlike the rapid change seen in histone modifications, global hypomethylation was observed four days after injury. DNA methylation level was restored beginning on day seven. The authors postulated that this time-dependent methylation change might be involved in the inflammatory processes which aid repair and recovery following injury.
Based on Zhang et al.’s observation, Lundberg et al. investigated the molecular mechanism leading to epigenetic changes following head injury. They found that Dnmt1 relocalized from the nuclei of neurons to the cytoplasm of astrocytes, also in a time-dependent manner post-injury (Lundberg et al., 2009). Dnmt1 or DNA methyltransferase-1 enzyme is responsible for catalyzing the addition of methyl group on cytosines and is critical for the faithful maintenance of DNA methylation during cell division. Interestingly, cells containing cytoplasmic Dnmt1 in Lundberg et al.’s model were not dividing. This result, along with Zhang et al.’s observation that no significant DNA methylation changes occurred in astrocytes specifically, suggests that Dnmt1 relocalization to astrocytes may serve to mediate other signaling pathway rather than directly regulating overall global DNA methylation changes in the brain.
Epigenetic processes mediate gene response to changes in tissue environment and overtime, confer memory of whether a gene is expressed or silenced. Comprehensive investigation of how these processes are altered during brain trauma is an important step in understanding the biological mechanism of injury and repair, which ultimately is essential for therapeutic development and risk management.
Daneshvar, D. H., Nowinski, C. J., McKee, A. C., and Cantu, R. C. (2011). The epidemiology of sport-related concussion. Clinics in sports medicine 30, 1-17, vii.
Gao, W. M., Chadha, M. S., Kline, A. E., Clark, R. S., Kochanek, P. M., Dixon, C. E., and Jenkins, L. W. (2006). Immunohistochemical analysis of histone H3 acetylation and methylation–evidence for altered epigenetic signaling following traumatic brain injury in immature rats. Brain research 1070, 31-34.
Griesbach, G. S., Hovda, D. A., Molteni, R., and Gomez-Pinilla, F. (2002). Alterations in BDNF and synapsin I within the occipital cortex and hippocampus after mild traumatic brain injury in the developing rat: reflections of injury-induced neuroplasticity. Journal of neurotrauma 19, 803-814.
Lundberg, J., Karimi, M., von Gertten, C., Holmin, S., Ekstrom, T. J., and Sandberg-Nordqvist, A. C. (2009). Traumatic brain injury induces relocalization of DNA-methyltransferase 1. Neuroscience letters 457, 8-11.
Takai, D., and Jones, P. A. (2002). Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proceedings of the National Academy of Sciences of the United States of America 99, 3740-3745.
Terrell, T. R., Bostick, R. M., Abramson, R., Xie, D., Barfield, W., Cantu, R., Stanek, M., and Ewing, T. (2008). APOE, APOE promoter, and Tau genotypes and risk for concussion in college athletes. Clinical journal of sport medicine: official journal of the Canadian Academy of Sport Medicine 18, 10-17.
Tierney, R. T., Mansell, J. L., Higgins, M., McDevitt, J. K., Toone, N., Gaughan, J. P., Mishra, A., and Krynetskiy, E. (2010). Apolipoprotein E genotype and concussion in college athletes. Clinical journal of sport medicine: official journal of the Canadian Academy of Sport Medicine 20, 464-468.
Yu, C. E., Cudaback, E., Foraker, J., Thomson, Z., Leong, L., Lutz, F., Gill, J. A., Saxton, A., Kraemer, B., Navas, P., et al. (2013). Epigenetic signature and enhancer activity of the human APOE gene. Human molecular genetics 22, 5036-5047.
Zhang, Z. Y., Zhang, Z., Fauser, U., and Schluesener, H. J. (2007). Global hypomethylation defines a sub-population of reactive microglia/macrophages in experimental traumatic brain injury. Neuroscience letters 429, 1-6.