Epigenetic Synthesis

First and foremost, what is epigenetics? Epigenetics is described as the study of gene expression changes without involving the changes in DNA sequence. The word “epigenetics” originates from the theory of epigenesis. The theory of epigenesis states that an embryo develops progressively from an undifferentiated egg cell. Epigenetics is a mechanism for mediating gene activity independent of DNA sequence determining which genes are turned on and which genes are turned off. (Holliday, 1994) This mechanism therefore plays a key role in the onset of many complex diseases, like for instance cancer. DNA methylation is a crucial epigenetic modification of the genome that is involved in regulating many cellular processes. Basically, DNA methylation

NAT. REV. GENETICS 8 (4), 286–298 (2007))

Histone proteins, consist of a globular C-terminal domain and an unstructured N-terminal tail. The N-terminal tail of histones can undergo a variety of changes which include methylation and acetylation. These modifications mediate and control key cellular processes such as transcription, replication and repair within the human genome. (Sharma et al., 2010) In contrast to DNA methylation, histone modifications can result in activation or repression depending on which regions are modified and also the type of modifications present. (Sharma et al., 2010)

Various changes in histone modification occur in cancer. For instance, loss of histone acetylation, which is controlled by histone deacetylases (HDACs) results in gene repression. Oftentimes, HDACs are found to be profoundly overexpressed in various forms of cancer. (Song et al., 2005) Histone acetyltransferases (HATs) which together with HDACs function in the process of histone acetylation are too altered aberrantly in cancer. (Yang, 2004) As well as changes in histone acetylation, alterations also occur in histone methylation patterns. Such changes in methylation patterns are linked with aberrant gene silencing in various types of cancer. In fact, the dysregulation of histone methyltransferases (HMTs) can result in the abnormal silencing of tumour suppressor genes. (Sharma et al.,

Epigenetic modifications in DNA methylation and the modifications of histones at the D4Z4 repeat array in FSHD are what cause the onset of this disease. In most cases, carriers of the disease with D4Z4 repeat sizes between 10 and 20 kb are seriously affected and exhibit very low DNA methylation levels, and patients with repeat sizes between 20 and 31 kb show large variation between cases in both clinical severity and D4Z4 hypomethylation. (de Greef et al., 2008) Particular histone modifications appear to be connected with activation or transcriptional repression. Methylation at certain lysine residues of histone H3 has been linked with transcriptional activation. Acetylation of arginine residues of histone H3 and H4 is too correlated with the initiation of genes. On the other hand, methylation at other lysine residues of histone H3 and at lysine residues of histone H4 has been linked to gene suppression. (Lachner et al.,