Controlling Long-Range Genomic Interactions at a Native Locus by Targeted Tethering of a Looping Factor

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• 作者：Wulan Deng¹ ; ² ; Jongjoo Lee⁴ ; Hongxin Wang¹ ; Jeff Miller⁵ ; Andreas Reik⁵ ; Philip&#160 ; D. Gregory⁵ ; Ann Dean⁴ ; Gerd&#160 ; A. Blobel¹ ; ³ ; ^{blobel@email.chop.edu}
• 刊名：Cell
• 出版年：2012
• 期刊代码：50_00928674
• 类别：med
• 出版时间：8 June, 2012
• 卷：149
• 期：6
• 页码：1233-1244
• 文件大小：1967 K

摘要

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Summary

Chromatin loops juxtapose distal enhancers with active promoters, but their molecular architecture and relationship with transcription remain unclear. In erythroid cells, the locus control region (LCR) and 尾-globin promoter form a chromatin loop that requires transcription factor GATA1 and the associated molecule Ldb1. We employed artificial zinc fingers (ZF) to tether Ldb1 to the 尾-globin promoter in GATA1 null erythroblasts, in which the 尾-globin locus is relaxed and inactive. Remarkably, targeting Ldb1 or only its self-association domain to the 尾-globin promoter substantially activated 尾-globin transcription in the absence of GATA1. Promoter-tethered Ldb1 interacted with endogenous Ldb1 complexes at the LCR to form a chromatin loop, causing recruitment and phosphorylation of RNA polymerase II. ZF-Ldb1 proteins were inactive at alleles lacking the LCR, demonstrating that their activities depend on long-range interactions. Our findings establish Ldb1 as a critical effector of GATA1-mediated loop formation and indicate that chromatin looping causally underlies gene regulation.

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