ABSTRACT
In this review the term epigenetics is used to describe features that function in addition to the genome (genotype) to influence a clinical readout (phenotype). These include histone and non-histone proteins and noncoding RNA transcripts that together comprise the chromatin, or epigenome, the packaged form of the DNA in the nucleus. The DNA, RNA and protein components of chromatin undergo differential chemical modifications, such as acetylation and methylation, dependent on the availability of the central metabolites acetyl-CoA and S-adenosylmethionine, which often reflect events in the chromatin such as transcription, replication, repair and cell division. Changes in the DNA sequence, transcript levels, proteins, DNA methylation or histone modifications in isolation can show some association with a clinical readout, but these are often not strong enough to act as robust biomarkers. However, robust epigenetic biomarkers are formed by integrating information about gene expression, genetics (SNPs, eQPLs, pQTLs, hQTLs), the metabolome and the epigenome. In nature, these features naturally combine to determine the 3D chromatin organization in the nucleus. Units of chromatin folding, known as chromosome conformation signatures, represent the smallest unit in the 3D genome that accurately reflects a clinical readout and provides new robust epigenetic biomarkers for personalized medicine.
