Role of Epigenetic Histone Modifications in the Expression and Treatment of Neurological Symptoms in Gulf War Illness
Abstract
Over two decades have passed since the completion of the Persian Gulf War, and we still do not have a clear understanding of the pathobiology of Gulf War Illness (GWI). Consequently, effective treatments for the management of GWI are not available. Despite several postulated mechanisms for GWI, a central question still remains: How can a chemical exposure from 25 years ago still produce a chronic multi-symptom illness even when the precipitating factors from the Iraqi War theatre are no longer present? This represents a major challenge in understanding the pathogenesis of GWI. Fiscal Year 2017 Gulf War Illness Research Program has recognized this as a topic of special interest. Epigenetics could provide novel insights into this perplexing question. Epigenetics is the study of changes in gene expression without a change in the DNA sequence. Simply put, epigenetics directs how genes are read by cells. Various circumstances can turn genes “on,” making them active, or turn genes “off,” making them dormant. Research has shown that these epigenetic changes can persist even in the absence of the initial factors that triggered them. Thus, understanding the epigenetic modifications that occur in GWI can offer important insight into the pathobiology of GWI. Interestingly, much as epigenetic mechanisms may adapt to environmental stimuli, they may be further modified and even reversed by other stimuli, including drugs. Therefore, targeting epigenetic changes can lead to treatment options that effectively treat GWI symptoms. Epigenetic changes are a natural and normal occurrence that can be influenced by many factors such as environment, diet, and experiences. Epigenetic mechanisms respond to these external stimuli, and the effects of such exposures can become embedded in the genome to produce long-lasting changes in cellular regulation. Sometimes, however, noxious stimuli can lead to maladaptive epigenetic responses that bring about neurological disorders such as depression or drug addiction. Indeed, recent research has indicated that epigenetic alterations may mediate toxicity from pesticides and may be involved in the development of depression. Thus, epigenetics is a powerful tool that can help us better understand GWI. There are several epigenetic mechanisms, including histone modifications, DNA methylation, and microRNA expression that switch genes “on” or “off.” Histone modification has been implicated in neurological disorders including depression, Alzheimer’s diseases, and epilepsy. Interestingly, these diseases share a similar symptomatology with GWI. However, presently there are no studies that have investigated the role of histone modifications in GWI. This is an important knowledge gap in GWI research. Our study is the first attempt to investigate whether histone modification themed neuro-epigenetic changes represent a causal link between organophosphate exposure and development of GWI neurological morbidities. Using advanced epigenome screening techniques, our preliminary research has observed major alterations in histone mechanisms. Interestingly, treatment with Food and Drug Administration (FDA)-approved drug valproic acid, a known inhibitor of histone modification enzymes, effectively lowered symptoms of depression and anxiety in an animal model of GWI. Given the long history of clinical use of valproic acid and available safety data, there is a high probability that valproic acid could be fast-tracked through the FDA and made available for our GWI Veterans. This translational research will have major clinical ramifications for treating GWI depression and related neurological comorbidities and would represent a major advance in the field. The proposed study is also highly innovative because it will provide initial data on the importance of the epigenome in the development and treatment of GWI. This study will examine only a handful of important genes, but there are thousands of other genes
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810190
Entities
People
- Laxmikant S. Deshpande
Organizations
- United States Army
- Virginia Commonwealth University