The neurosurgical role of epigenome☆

A relatively new word epigenome is getting attention everyday, and many basic scientists or even surgeons are talking about it. What is epigenome and what is its role in the future neurosurgery?

In the early 1940s, Conrad H. Waddington originally defined epigenetics as “the interactions of genes with their environment that bring the phenotype into being.” Epigenetic processes control the packaging and function of the human genome and contribute to not only normal states such as development, chromosome stability, and maintaining gene expression but also pathologic conditions, including the development of human tumors [1], [2], [7]. Basically, today, epigenetic research focused on the discovery of factors that are essential regulators for genome structure and gene expression, and the recognition of environmental factors can change the way genes are expressed.

The genome, the complete set of genetic information contained in the DNA of an organism, is programmed by the epigenome, which controls the differential expression of genes in specific cells. Basically, epigenetics is defined as heritable changes in gene expression without directly affecting and mutating the sequence of the DNA. There are 2 epigenetic mechanisms, DNA methylation and histone code alterations, which manifest in both global changes in chromatin packaging and in localized gene promoter changes. There is a close interplay between these aberrant epigenetic changes, which are linked to gene activation, gene silencing, and chromosomal instability [1], [5].

It is well established that severely disrupted DNA methylation patterns play important role in tumor formation [2], [7]. This is very similar to that of genetic mutations in cancer; however, unlike a genetic alteration, DNA methylation is potentially reversible with pharmacologic intervention [8]. Hence, it represents an attractive therapeutic target for human cancer therapy. For example, a lack of the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT), which is frequent in glioma, may be caused by such an epigenetic modifications rather than mutation or deletion of MGMT gene. Silencing of MGMT by DNA methylation has been reported to be associated with regression of the tumor and prolonged overall and disease-free survival [3], [4]. Not surprisingly, molecular information provided by genomic technologies will provide a remarkable opportunity for discovering these new targets.

Genetic and epigenetic mechanisms both contribute to and likely interact during tumorigenesis [2], [7]. However, more important, the epigenome can change according to an individual's environment and is transmitted to the next generation. For example, a recent study provided evidence that epigenetic transgenerational inheritance can occur in humans in response to food supply and smoking [6]. Although, theoretically, environmental exposure to nutritional, chemical, and physical factors can alter the epigenome, and certain epigenetic alleles can be inherited that affect tumor suppressor genes [5], it is still unknown and under investigation whether environmentally induced epigenetic changes in gene regulation are involved in the formation of human central nervous system tumors. However, in the future, exploring such a connection would result in novel ways not only to treat but also to prevent these life-threatening diseases.