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

Estrogens (E2) and retinoic acid (RA) bind their receptors and assemble the transcription initiation complex at specific DNA sites (ERE or RARE). To analyze the association between transcription, histone modifications and chromatin remodeling, we used 4 estrogen- and retinoic prototypic genes, which are induced by E2 and RA, respectively. We found that upon activation of estrogen receptor, at the ERE-RARE promoters chromatin, histone H3 lysines 9 and 4 undergo cycles of methylation and demethylation. The lysine specific demethylase LSD1, recruited at ERE-RARE sites following hormone induction, sets off an oxidation wave that modifies the DNA locally and recruits the enzymes, involved in base and nucleotide excision repair (BER-NER). One important result of histone H3K9-K4 demethylation is DNA oxidation, which leads to the formation of 8oxo-guanine, which bends the helix and is rapidly recognized by the 8‐oxoG glycosylase, OGG1. dG oxidation and repair proceed in a strand specific fashion at the ERE-RARE, transcription start sites (TSS) and poly_A addition sites. DNA oxidation and concerted repair are essential for the formation of chromatin loop(s) juxtaposing the ERE‐RARE with TSS and the 3’ end of the genes. The loops undergo cycles (approx. 45-60 min) as well as histone H3K4-K9 methylation and demethylation. The driver of the cycles appear to be the demethylating enzyme, LSD1, because its inhibition by a dominant negative mutants or its depletion, disrupt methylation-demethylation cycles, desynchronize loop formation and inhibit productive RA or E2‐induced transcription.