Poster Presentation 46th Lorne Genome Conference 2025

Nucleosome eviction at tet/tdg-targeted enhancers occurs independently of the removal of the chromatin mark oxidized-methylcytosine (#245)

Marion Turpin 1 , Thierry Madigou 2 , Rachael Acker 2 3 , Maud Bizot 2 , Katie Sawvell 2 4 , Stephane Avner 2 , Audrey Laurent 2 , Gaelle Palierne 2 , Christine Le Peron 2 , Gilles Salbert 2
  1. South Australian immunoGENomics Cancer Institute, Adelaide, SA, Australia
  2. Université de Rennes, CNRS, Institut de Génétique et Développement de Rennes, UMR 6290, 35000 Rennes, Ille-et-Vilaine, France
  3. University of Pennsylvania, Philaldelphia, PennSylvania, USA
  4. Cincinnati Children’s Hospital Medical Center, U.S, Cincinnati, Ohio, USA

Genome-wide CpG methylation patterns reflect the competing action of DNA methyltransferases (DNMTs) and demethylation mechanisms, relying in part on 5-methylcytosine (5mC) oxidation by Ten-Eleven-Translocation (TET) enzymes. CpG methylation patterns can reflect cell-specific transcriptional programs and besides depending on DNMTs and TETs, these patterns can also be regulated locally by the engagement of transcription factors (TFs). This can be observed at small genomic regulatory regions called enhancers which undergo 5mC oxidation upon TF binding and recruitment of TETs. However, it remains unclear how 5mC oxidation functionally relates to enhancers, and what are the mechanisms underlying the successive oxidative steps. In this respect, priming is linked to the first step of 5mC oxidation into 5-hydroxymethylcytosine (5hmC), and further oxidation into 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) correlate with enhancer activation. However, it is unknown whether removal of oxidized bases (oxi-mCs) is required for enhancer activation. Elimination of oxi-mCs in cycling cells can either occur through a passive mechanism of cell division, or the recognition of 5fC/5caC as DNA damages and their active removal by the T:G mismatch DNA glycosylase (TDG)/base excision repair (BER) machinery. Here, we identified enhancers undergoing a TET/TDG-dependent full demethylation process during differentiation of pluripotent embryonal carcinoma cells into neural progenitor-like cells (NPCs), through genome-wide mapping of 5caC in TDG null cells.  The impact of oxi-mC persistence on the chromatin structure of these enhancers was analyzed by MNase-seq and -qPCR assays. We identified hundreds of enhancers undergoing TDG-dependent oxi-mC removal during differentiation but observed that these regions undergo nucleosome eviction even without oxi-mC removal. Hence, we conclude that neural enhancer activation is linked to oxi-mC occurrence but does not require their removal by TDG.