Mechanism of retinoic acid-induced transcription: histone code, DNA oxidation and formation of chromatin loops

Histone methylation changes and formation of chro- matin loops involving enhancers, promoters and 3′ end regions of genes have been variously associ- ated with active transcription in eukaryotes. We have studied the effect of activation of the retinoic A re- ceptor, at the RARE–promoter chromatin of CASP9 and CYP26A1 genes, 15 and 45 min following RA ex- posure, and we found that histone H3 lysines 4 and 9 are demethylated by the lysine-specific demethylase, LSD1 and by the JMJ-domain containing demethy- lase, D2A. The action of the oxidase (LSD1) and a dioxygenase (JMJD2A) in the presence of Fe++ elic- its an oxidation wave that locally modifies the DNA and recruits the enzymes involved in base and nu- cleotide excision repair (BER and NER). These events are essential for the formation of chromatin loop(s) that juxtapose the RARE element with the 5′ tran- scription start site and the 3′ end of the genes. The RARE bound-receptor governs the 5′ and 3′ end se- lection and directs the productive transcription cycle of RNA polymerase. These data mechanistically link chromatin loops, histone methylation changes and localized DNA repair with transcription.