The second dimension of the genetic code

DNA stores genetic information in the sequence of the four canonical bases dA, dC, dG, and T and, in addition, carries epigenetic information encoded by the four modified cytidine bases: 5-methylcytidine (mdC), 5-hydroxymethylcytidine (hmdC), 5-formylcytidine (fdC), and 5-carboxycytidine (cadC), with 5-hydroxymethyluridine (hmdU) potentially playing a role as well. These additional nucleosides are generated by TET(1-3) enzymes, which catalyze the stepwise oxidation of mdC or T to all the others, with the help of oxygen and -ketoglutarate. This oxidation chemistry in the genome thus establishes a second, largely uncharted layer of information. While the sequence code is static, the writing and erasure of the epigenetic code creates a dynamic information layer that controls gene activity, e.g. the differentiation of cells or memory formation and erasure in the brain. In this lecture, I will cover the discovery of the new epigenetic bases that expand the genetic alphabet using quantitative mass spectrometry and I will discuss new insights into their symmetry and localization based on recent sequencing data. I will then describe how the TET-based chemistry is now being exploited to develop new epigenetic sequencing methods that enable earlier cancer detection, thereby improving the chances of successful treatment. If time permits, I will also discuss why the modified base pseudouridine in mRNA allows the molecule to evade the innate immune system.

Speaker: Thomas Carell, Ludwig Maximilian University, München