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    • DNA methylation is a major epigenetic mechanism responsible

    2018-11-07

    DNA methylation is a major epigenetic mechanism responsible for changing the program of genes thus deviating towards disease states (Lardenoije et al., 2015; Szyf et al., 2016). An increasing body of evidence indicates that predisposition to various neurological and psychiatric disorders are saved as epigenetic modifications (Jakovcevski and Akbarian, 2012; Tsankova et al., 2007), and blast exposure results in changes in neuronal DNA methylation (Haghighi et al., 2015). Our results showing the impact of TBI on DNA methylation of multiple genes in both hippocampus and leukocytes provide the opportunity to examine how the effects of TBI can be saved with the potential to regulate gene transcription. Indeed, the action of TBI on the epigenome was revealed on select DNA methylomic alterations that co-localized and correlated with transcriptomic signature genes. It should be noted that correlation is not equal to causality and further validation experiments are warranted to investigate the causal relationship between the epigenome and the transcriptome. Alternative splicing is emerging as another gene regulatory mechanism by which the genome influences the etiology of various diseases such as AD (Xiong et al., 2015). Our results show that TBI affects numerous alternatively spliced genes in the hippocampus and leukocytes involved in functions such as coagulation, blood pressure, inflammation, pacap management, and ECM regulation. Further examination of these genes could guide the identification of particularly vulnerable points and mechanisms through which the TBI pathology could deviate to other disorders. For example, many of the signature genes are known splicing regulators such as Rbm47, Sfrs18, Snrnp40, and Uhmk1. Among these, Uhmk1 has been recently related to genetic disposition to cerebral visual impairment (Bosch et al., 2016) while Rbm47 confers genetic risk to high blood pressure and cardiovascular disease (Surendran et al., 2016), and both traits are common aspects of TBI pathology. Our results portray both epigenomic modification and alternative splicing events as putative mechanisms by which TBI impacts gene network programming and disease predisposition. To date, perturbations in gene network regulation has also been recognized as a key component of the pathogenesis of neurological disorders (Narayanan et al., 2014; Zhang et al., 2013). We identified the impact of TBI on the organization of select networks of genes under regulatory control of key driver genes, which may be responsible for the cascade of cellular events involved in the TBI pathology. We found that TBI affects hippocampal and leukocyte gene networks orchestrated by key driver genes associated with the extracellular matrix (e.g., Fmod, Dcn, Pcolce, collagens), transcription factors (e.g., Tcf7l2, Cebpd), and other functions discussed below (e.g., Anxa2, Ogn). These master genes are located at the center of gene subnetworks surrounded by TBI signature genes, and are likely key regulatory points of these networks. The extracellular matrix genes Fmod and Pcolce have been recently experimentally validated as key regulators of cognitive and metabolic functions (Meng et al., 2016). Tcf7l2 and Cebpd are key transcription factors involved in metabolic processes, diabetes and fat differentiation. The key driver Anxa2 (annexin A2) has been associated with brain tumor formation (Zhai et al., 2011) and the long-term neurological outcomes of focal embolic stroke (Wang et al., 2014). In turn, the fact that Ogn (osteoglycin) is reduced in the amygdala of animals exposed to stress (Jung et al., 2012), suggests that this gene can be an important link between TBI and psychiatric-like disorders such as anxiety and depression (Max, 2014). The fact that TBI-affected genes are tightly connected through key drivers in gene regulatory networks constructed from completely independent studies supports their functional relatedness and their synchronized actions. The identification of key regulatory genes of the entire network spectrum affected by TBI provides a framework for understanding the integrated actions of multiple pathways on the TBI pathology, and offers plausible key interventional targets (Kasarskis et al., 2011; Yang et al., 2012; Schadt et al., 2009).