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Hsu PY , Hsu HK , Singer GAC , Yan PS , Rodriguez BAT , Liu JC , Weng YI , Deatherage DE , Chen Z , Pereira JS , Lopez R , Russo J , Wang QB , Lamartiniere CA , Nephew KP , Huang THM
Estrogen-mediated epigenetic repression of large chromosomal regions through DNA looping
Genome Research. 2010 Jun;20(6) :733-744
PMCID: PMC2877570   
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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 similar to 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.
Hsu, Pei-Yin Hsu, Hang-Kai Singer, Gregory A. C. Yan, Pearlly S. Rodriguez, Benjamin A. T. Liu, Joseph C. Weng, Yu-I Deatherage, Daniel E. Chen, Zhong Pereira, Julia S. Lopez, Ricardo Russo, Jose Wang, Qianben Lamartiniere, Coral A. Nephew, Kenneth P. Huang, Tim H. -M. Cold spring harbor lab press, publications dept Woodbury 604hf