DNA oxidation as triggered by H3K9me2 demethylation drives estrogen-induced gene expression

Bruno Perillo; Maria Neve Ombra; Alessandra Bertoni; Concetta Cuozzo; Silvana Sacchetti; Annarita Sasso; Lorenzo Chiariotti; Antonio Malorni; Ciro Abbondanza; Enrico V Avvedimento

doi:10.1126/science.1147674

DNA oxidation as triggered by H3K9me2 demethylation drives estrogen-induced gene expression

Science. 2008 Jan 11;319(5860):202-6. doi: 10.1126/science.1147674.

Authors

Bruno Perillo¹, Maria Neve Ombra, Alessandra Bertoni, Concetta Cuozzo, Silvana Sacchetti, Annarita Sasso, Lorenzo Chiariotti, Antonio Malorni, Ciro Abbondanza, Enrico V Avvedimento

Affiliation

¹ Istituto di Scienze dell'Alimentazione, Consiglio Nazionale delle Ricerche (C.N.R.), 83100 Avellino, Italy. [email protected]

PMID: 18187655
DOI: 10.1126/science.1147674

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cells, Cultured
Chromatin / metabolism
DNA / metabolism*
DNA Damage
DNA Glycosylases / metabolism
DNA Repair
DNA Topoisomerases, Type II / metabolism
DNA-Binding Proteins / metabolism
Enhancer Elements, Genetic
Estradiol / metabolism*
Estrogen Receptor alpha / metabolism
Gene Expression Regulation*
Genes, bcl-2
Guanine / analogs & derivatives
Guanine / metabolism
Histone Demethylases
Histones / metabolism*
Humans
Hydrogen Peroxide / metabolism
Lysine / metabolism
Methylation
Nucleic Acid Conformation
Oxidation-Reduction
Oxidoreductases, N-Demethylating / metabolism
Promoter Regions, Genetic
RNA Polymerase II / metabolism
Transcription, Genetic*

Substances

Chromatin
DNA-Binding Proteins
Estrogen Receptor alpha
Histones
Estradiol
8-hydroxyguanine
Guanine
DNA
Hydrogen Peroxide
Histone Demethylases
KDM1A protein, human
Oxidoreductases, N-Demethylating
RNA Polymerase II
DNA Glycosylases
oxoguanine glycosylase 1, human
DNA Topoisomerases, Type II
Lysine