DNA oxidation as triggered by H3K9me2 demethylation drives estrogen-induced gene expression.
Modifications at the N-terminal tails of nucleosomal histones are required for efficient transcription in vivo. We analyzed how H3 histone methylation and demethylation control expression of estrogen-responsive genes and show that a DNA-bound estrogen receptor directs transcription by participating in bending chromatin to contact the RNA polymerase II recruited to the promoter. This process is driven by receptor-targeted demethylation of H3 lysine 9 at both enhancer and promoter sites and is achieved by activation of resident LSD1 demethylase. Localized demethylation produces hydrogen peroxide, which modifies the surrounding DNA and recruits 8-oxoguanine-DNA glycosylase 1 and topoisomeraseIIbeta, triggering chromatin and DNA conformational changes that are essential for estrogen-induced transcription. Our data show a strategy that uses controlled DNA damage and repair to guide productive transcription.
Perillo
Bruno
B
Istituto di Scienze dell'Alimentazione, Consiglio Nazionale delle Ricerche (C.N.R.), 83100 Avellino, Italy. perillo@unina.it
Ombra
Maria Neve
MN
Bertoni
Alessandra
A
Cuozzo
Concetta
C
Sacchetti
Silvana
S
Sasso
Annarita
A
Chiariotti
Lorenzo
L
Malorni
Antonio
A
Abbondanza
Ciro
C
Avvedimento
Enrico V
EV
D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism; D004260:DNA Repair; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D004958:Estradiol / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005786:Gene Expression Regulation; D019254:Genes, bcl-2; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D056466:Histone Demethylases; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D009690:Nucleic Acid Conformation; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D014158:Transcription, Genetic
D002843:Chromatin; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D006657:Histones; D004958:Estradiol; C024829:8-hydroxyguanine; D006147:Guanine; D004247:DNA; D006861:Hydrogen Peroxide; D056466:Histone Demethylases; C495195:KDM1A protein, human; D010089:Oxidoreductases, N-Demethylating; D012319:RNA Polymerase II; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D004250:DNA Topoisomerases, Type II; D008239:Lysine