Epigenetics in disease and the promise of therapy
Known epigenetic changes typically occur in normal development, regulating the normaldifferential expression and silencing of genes. However, certain epigenetic alterations have been implicated in disease. Specifically, a disruption in any of the epigenetics “systems”, DNA methylation, histone modifications, transcription factor binding, and RNA-associated silencing can cause abnormal gene silencing or expression leading to undesirable consequences such as cancer, mental disabilities such as Fragile X, Angelman’s, and Prader-Willi syndromes, as well as other diseases that result from chromosomal instability.
As an example, tumorigenesis in a number of cancers have been linked to abnormal DNA methylation. DNA methylation occurs at CpG sites in the genome. Areas near gene promoters with high concentrations of CpGs are unmethylated in normal cells. In cancer cells, CpG islands have excessive methylation and may cause gene silencing which in turn may shut off tumor suppressor genes. Hypermethylation can also lead to microsatellite instability which has been linked to colorectal, endometrial, ovarian, and gastric cancers (Jones & Baylin, 2002).
A number of mental disabilities have also been associated with epigenetic changes. Fragile X syndrome which causes delayed mental development is caused by excessive methylation in the CpG islands of the promoter of the FMR1 gene, turning it off, and thereby producing the disorder. Similar conditions include Rubenstein-Taybi and Coffin-Lowry syndromes which are linked to irregular histone modifications (Penagarikano et al., 2007).
As many disease states are linked to epigenetic disruptions, it has increasingly become important to analyze specific modifications with the eventual goal of devising targeted therapeutics. Unlike DNA sequence mutations, epigenetic modifications are reversible and potential treatments could be geared to alter irregular transcription factor binding, DNA methylation or histone acetylation. Accurate study with a versatile number of tools is essential for the study of epigenetics including sound sample preparation and analysis methodologies for DNA methylation such as with immunoprecipitation or bisulfite sequencing, chromatin analysis with chromatin immunoprecipitation (ChIP) combined with qPCR or sequencing, and RNA modification study. As researchers elucidate the mechanisms and specific modifications associated with disease, it may be possible to target abnormal modifications in cells with minimal damage to normal cells, making the prospect of epigenetic therapy increasingly promising.
Rini Saxena, VP Marketing & Commercialization at Diagenode