Estrogen-mediated epigenetic repression of large chromosomal regions through DNA looping
- Pei-Yin Hsu1,
- Hang-Kai Hsu1,
- Gregory A.C. Singer1,
- Pearlly S. Yan1,
- Benjamin A.T. Rodriguez1,
- Joseph C. Liu1,
- Yu-I Weng1,
- Daniel E. Deatherage1,
- Zhong Chen2,
- Julia S. Pereira3,
- Ricardo Lopez3,
- Jose Russo3,
- Qianben Wang2,
- Coral A. Lamartiniere4,
- Kenneth P. Nephew5 and
- Tim H.-M. Huang1,6
- 1 Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, USA;
- 2 Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio 43210, USA;
- 3 Breast Cancer Research Laboratory, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA;
- 4 Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA;
- 5 Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana 47405, USA
Abstract
The current concept of epigenetic repression is based on one repressor unit corresponding to one silent gene. This notion, however, cannot adequately explain concurrent silencing of multiple loci observed in large chromosome regions. The long-range epigenetic silencing (LRES) can be a frequent occurrence throughout the human genome. To comprehensively characterize the influence of estrogen signaling on LRES, we analyzed transcriptome, methylome, and estrogen receptor alpha (ESR1)-binding datasets from normal breast epithelia and breast cancer cells. This “omics” approach uncovered 11 large repressive zones (range, 0.35∼5.98 megabases), including a 14-gene cluster located on 16p11.2. In normal cells, estrogen signaling induced transient formation of multiple DNA loops in the 16p11.2 region by bringing 14 distant loci to focal ESR1-docking sites for coordinate repression. However, the plasticity of this free DNA movement was reduced in breast cancer cells. Together with the acquisition of DNA methylation and repressive chromatin modifications at the 16p11.2 loci, an inflexible DNA scaffold may be a novel determinant used by breast cancer cells to reinforce estrogen-mediated repression.
Footnotes
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↵6 Corresponding author.
E-mail tim.huang{at}osumc.edu.
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[Supplemental material is available online at http://www.genome.org. The sequencing and microarray data from this study have been submitted to the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo) under accession no. GSE21068.]
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Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.101923.109.
- Received October 14, 2009.
- Accepted March 17, 2010.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press