Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Logo for

Science 319 (5860): 202-206

Copyright © 2008 by the American Association for the Advancement of Science

DNA Oxidation as Triggered by H3K9me2 Demethylation Drives Estrogen-Induced Gene Expression

Bruno Perillo,1*{dagger} Maria Neve Ombra,1* Alessandra Bertoni,2 Concetta Cuozzo,3 Silvana Sacchetti,3 Annarita Sasso,2 Lorenzo Chiariotti,2 Antonio Malorni,1 Ciro Abbondanza,4 Enrico V. Avvedimento2{dagger}

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 topoisomeraseIIβ, 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.

1 Istituto di Scienze dell'Alimentazione, Consiglio Nazionale delle Ricerche (C.N.R.), 83100 Avellino, Italy.
2 Dipartimento di Biologia e Patologia Cellulare e Molecolare "L. Califano," Università degli Studi "Federico II," 80131 Naples, Italy.
3 Naples Oncogenomic Center, Centro di Ingegneria Genetica (CEINGE), Biotecnologie Avanzate, 80131 Naples, Italy.
4 Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, 80138 Naples, Italy.

* These authors contributed equally to this paper.

{dagger} To whom correspondence should be addressed. E-mail: perillo{at}unina.it (B.P.); avvedim{at}unina.it (E.V.A.)

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Close encounters of the 3C kind: long-range chromatin interactions and transcriptional regulation.
R.-J. T. S. Palstra (2009)
Brief Funct Genomic Proteomic
   Abstract »    Full Text »    PDF »
Estrogen Receptor {alpha} Enhances the Rate of Oxidative DNA Damage by Targeting an Equine Estrogen Catechol Metabolite to the Nucleus.
Z. Wang, G. T. Wijewickrama, K.-w. Peng, B. M. Dietz, L. Yuan, R. B. van Breemen, J. L. Bolton, and G. R. J. Thatcher (2009)
J. Biol. Chem. 284, 8633-8642
   Abstract »    Full Text »    PDF »
Cyclical Chromatin Looping and Transcription Factor Association on the Regulatory Regions of the p21 (CDKN1A) Gene in Response to 1{alpha},25-Dihydroxyvitamin D3.
A. Saramaki, S. Diermeier, R. Kellner, H. Laitinen, S. Vaisanen, and C. Carlberg (2009)
J. Biol. Chem. 284, 8073-8082
   Abstract »    Full Text »    PDF »
Developmental roles of the histone lysine demethylases.
A. Nottke, M. P. Colaiacovo, and Y. Shi (2009)
Development 136, 879-889
   Abstract »    Full Text »    PDF »
Oxidative Stress in Developmental Origins of Disease: Teratogenesis, Neurodevelopmental Deficits, and Cancer.
P. G. Wells, G. P. McCallum, C. S. Chen, J. T. Henderson, C. J. J. Lee, J. Perstin, T. J. Preston, M. J. Wiley, and A. W. Wong (2009)
Toxicol. Sci. 108, 4-18
   Abstract »    Full Text »    PDF »
Genetic factors contributing to obesity and body weight can act through mechanisms affecting muscle weight, fat weight, or both.
G. A. Brockmann, S.-W. Tsaih, C. Neuschl, G. A. Churchill, and R. Li (2009)
Physiol Genomics 36, 114-126
   Abstract »    Full Text »    PDF »
NF-Y substitutes H2A-H2B on active cell-cycle promoters: recruitment of CoREST-KDM1 and fine-tuning of H3 methylations.
R. Gatta and R. Mantovani (2008)
Nucleic Acids Res. 36, 6592-6607
   Abstract »    Full Text »    PDF »
Effects of Manganese Superoxide Dismutase Silencing on Androgen Receptor Function and Gene Regulation: Implications for Castration-Resistant Prostate Cancer.
N. Sharifi, E. M. Hurt, S. B. Thomas, and W. L. Farrar (2008)
Clin. Cancer Res. 14, 6073-6080
   Abstract »    Full Text »    PDF »
Estrogen Receptor-{alpha} and Endothelial Nitric Oxide Synthase Nuclear Complex Regulates Transcription of Human Telomerase.
A. Grasselli, S. Nanni, C. Colussi, A. Aiello, V. Benvenuti, G. Ragone, F. Moretti, A. Sacchi, S. Bacchetti, C. Gaetano, et al. (2008)
Circ. Res. 103, 34-42
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882