CTCF-dependent enhancer-blocking by alternative chromatin loop formation

被引:147
作者
Hou, Chunhui [1 ]
Zhao, Hui [1 ]
Tanimoto, Keiji [2 ]
Dean, Ann [1 ]
机构
[1] NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA
[2] Univ Tsukuba, Grad Sch Life & Environm Sci, Tsukuba, Ibaraki 3058577, Japan
基金
美国国家卫生研究院;
关键词
beta-globin genes; insulator; locus control region; epigenetics; transcription regulation;
D O I
10.1073/pnas.0808506106
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The mechanism underlying enhancer-blocking by insulators is unclear. We explored the activity of human beta-globin HS5, the orthologue of the CTCF-dependent chicken HS4 insulator. An extra copy of HS5 placed between the beta-globin locus control region (LCR) and downstream genes on a transgene fulfills the classic predictions for an enhancer-blocker. Ectopic HS5 does not perturb the LCR but blocks gene activation by interfering with RNA pol II, activator and coactivator recruitment, and epigenetic modification at the downstream beta-globin gene. Underlying these effects, ectopic HS5 disrupts chromatin loop formation between beta-globin and the LCR, and instead forms a new loop with endogenous HS5 that topologically isolates the LCR. Both enhancer-blocking and insulator-loop formation depend on an intact CTCF site in ectopic HS5 and are sensitive to knock-down of the CTCF protein by siRNA. Thus, intrinsic looping activity of CTCF sites can nullify LCR function.
引用
收藏
页码:20398 / 20403
页数:6
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