Estrogen-mediated epigenetic repression of large chromosomal regions through DNA looping

Pei Yin Hsu, Hang Kai Hsu, Gregory A.C. Singer, Pearlly S. Yan, Benjamin A.T. Rodriguez, Joseph C. Liu, Yu I. Weng, Daniel E. Deatherage, Zhong Chen, Julia S. Pereira, Ricardo Lopez, Jose Russo, Qianben Wang, Coral A. Lamartiniere, Kenneth P. Nephew, Tim H.M. Huang

Research output: Contribution to journalArticle

69 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)733-744
Number of pages12
JournalGenome research
Volume20
Issue number6
DOIs
StatePublished - Jun 1 2010

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Hsu, P. Y., Hsu, H. K., Singer, G. A. C., Yan, P. S., Rodriguez, B. A. T., Liu, J. C., Weng, Y. I., Deatherage, D. E., Chen, Z., Pereira, J. S., Lopez, R., Russo, J., Wang, Q., Lamartiniere, C. A., Nephew, K. P., & Huang, T. H. M. (2010). Estrogen-mediated epigenetic repression of large chromosomal regions through DNA looping. Genome research, 20(6), 733-744. https://doi.org/10.1101/gr.101923.109