Area A: Modifications on Nucleic Acids

Project A05 – Sequence specific and functional analysis of oxdative modifications in nucleic acids – implication for epigenetic memory in the mouse

Tet mediated oxidative modifications of 5-methylcytosine (5mC) regulate and modulate short term and long term effects of epigenetic memory. In this project we will study the DNA-methylation dynamics, driven by Tet mediated oxidation of 5mC to 5hmC/5fC/5caC using mouse ES cells and primary human cells. Towards this goal we will develop and apply novel multimodal NGS approaches for a simultaneous base specific detection of DNA-modifications (5mC, 5hmC and 5fC) and open chromatin (NoMe). Using these data we will model and interpret the dynamic processes regulated by the oxidative modifications. Complementary to this we will use a set of our mouse models bearing the designed mutations, disabling specific Tet3 isoforms to comprehensively analyse the role of Tet3 isoforms for the (dynamic) control of epigenetic programs and their consequences for transcription. Here we will focus on early mammalian development and on neuronal cell lineages, isolated from these mutant mice. We will apply molecular and NGS based approaches combined with integrative analyses to decipher the role of oxidative modifications on transcriptional control.