title: Estrogen-mediated epigenetic repression of large chromosomal regions through DNA looping.
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 approximately 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.
authors.affiliation: Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Pei-Yin
authors.initials: PY
authors.lastname: Hsu
authors.forename: Hang-Kai
authors.initials: HK
authors.lastname: Hsu
authors.forename: Gregory A C
authors.initials: GA
authors.lastname: Singer
authors.forename: Pearlly S
authors.initials: PS
authors.lastname: Yan
authors.forename: Benjamin A T
authors.initials: BA
authors.lastname: Rodriguez
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Liu
authors.forename: Yu-I
authors.initials: YI
authors.lastname: Weng
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Deatherage
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.forename: Julia S
authors.initials: JS
authors.lastname: Pereira
authors.forename: Ricardo
authors.initials: R
authors.lastname: Lopez
authors.forename: Jose
authors.initials: J
authors.lastname: Russo
authors.forename: Qianben
authors.initials: Q
authors.lastname: Wang
authors.forename: Coral A
authors.initials: CA
authors.lastname: Lamartiniere
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
authors.forename: Tim H-M
authors.initials: TH
authors.lastname: Huang
mesh_terms: D000818:Animals; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002885:Chromosomes, Human, Pair 16; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism / Q000502:physiology*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism; D005810:Multigene Family
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens