Local DNA oxidation and DNA methylation define chromatin loops and drive the transcription cycles induced by estrogen

Changes of histone methylation code, cytosine hydroxylation and chromatin loop formation are associated with transcription induction by nuclear hormones, but it is not known if these events are the consequence or the cause of transcription initiation. We show periodic oscillations of histone H3 methylation, G oxidation, C methylation and hydroxyl-methylation at the enhancer and polyA addition sites after induction of transcription in prototypic estrogen-induced genes. The oscillations correlate with formation of chromatin loops that juxtapose the 5' and 3' ends of the induced genes. BER followed by NER enzymes are recruited to the 5' and 3' end sites to repair the DNA oxidative lesions and to stabilize the 5' and 3' borders of the transcriptional units included in the loops. At the 5' end site of the loops, repair of oxidized Gs and hydroxymethylated Cs proceeds in a strand specific fashion. We suggest that coupling transcription with methylation and repair enzymes is the evolutionary strategy to reduce the mutational burder induced by DNA oxidation at the borders of chromatin loops.