Estrogen-mediated epigenetic repression of large chromosomal regions through DNA looping.
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.
Hsu
Pei-Yin
PY
Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, USA.
Hsu
Hang-Kai
HK
Singer
Gregory A C
GA
Yan
Pearlly S
PS
Rodriguez
Benjamin A T
BA
Liu
Joseph C
JC
Weng
Yu-I
YI
Deatherage
Daniel E
DE
Chen
Zhong
Z
Pereira
Julia S
JS
Lopez
Ricardo
R
Russo
Jose
J
Wang
Qianben
Q
Lamartiniere
Coral A
CA
Nephew
Kenneth P
KP
Huang
Tim H-M
TH
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
D047628:Estrogen Receptor alpha; D004967:Estrogens