CRISPR Inversion of CTCF Sites Alters Genome Topology and Enhancer/Promoter Function

被引：696

作者：

Guo, Ya ^{[1
,2
,3
]}

Xu, Quan ^{[1
,2
,3
]}

Canzio, Daniele ^{[4
]}

Shou, Jia ^{[1
,2
,3
]}

Li, Jinhuan ^{[1
,2
,3
]}

Gorkin, David U. ^{[5
,6
]}

Jung, Inkyung ^{[5
,6
]}

Wu, Haiyang ^{[1
,2
,3
]}

Zhai, Yanan ^{[1
,2
,3
]}

Tang, Yuanxiao ^{[1
,2
,3
]}

Lu, Yichao ^{[1
,2
,3
]}

Wu, Yonghu ^{[1
,2
,3
]}

Jia, Zhilian ^{[1
,2
,3
]}

Li, Wei ^{[1
,2
,3
]}

Zhang, Michael Q. ^{[7
,8
]}

Ren, Bing ^{[5
,6
]}

Krainer, Adrian R. ^{[9
]}

Maniatis, Tom ^{[4
]}

Wu, Qiang ^{[1
,2
,3
]}

机构：

[1] Shanghai Jiao Tong Univ, Collaborat Innovat Ctr Syst Biomed, Inst Syst Biomed, Ctr Comparat Biomed,MOE Key Lab Syst Biomed, Shanghai 200240, Peoples R China

[2] Shanghai Jiao Tong Univ, Sch Med, State Key Lab Oncogenes & Related Genes, Shanghai Canc Inst,Renji Hosp, Shanghai 200240, Peoples R China

[3] Shanghai Jiao Tong Univ, Sch Life Sci & Biotechnol, BioX Ctr, Key Lab Genet Dev & Neuropsychiat Disorders MOE, Shanghai 200240, Peoples R China

[4] Columbia Univ, Med Ctr, Dept Biochem & Mol Biophys, New York, NY 10032 USA

[5] Univ Calif San Diego, San Diego Sch Med, Ludwig Inst Canc Res, La Jolla, CA 92093 USA

[6] Univ Calif San Diego, San Diego Sch Med, Dept Cellular & Mol Med, La Jolla, CA 92093 USA

[7] Univ Texas Dallas, Dept Mol & Cell Biol, Ctr Syst Biol, Richardson, TX 75080 USA

[8] Tsinghua Univ, TNLIST Dept Automat, Ctr Synthet & Syst Biol, MOE Key Lab Bioinformat & Bioinformat Div, Beijing 100084, Peoples R China

[9] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

来源：

CELL | 2015年 / 162卷 / 04期

关键词：

PROTEIN-DNA INTERACTIONS; ALPHA GENE-CLUSTER; PROTOCADHERIN-ALPHA; GAMMA-PROTOCADHERINS; REGULATORY ELEMENTS; PROMOTER CHOICE; CELL-ADHESION; BINDING; BETA; ORGANIZATION;

D O I：

10.1016/j.cell.2015.07.038

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

CTCF and the associated cohesin complex play a central role in insulator function and higher-order chromatin organization of mammalian genomes. Recent studies identified a correlation between the orientation of CTCF-binding sites (CBSs) and chromatin loops. To test the functional significance of this observation, we combined CRISPR/Cas9-based genomic-DNA-fragment editing with chromosome-conformation-capture experiments to show that the location and relative orientations of CBSs determine the specificity of long-range chromatin looping in mammalian genomes, using protocadherin (Pcdh) and beta-globin as model genes. Inversion of CBS elements within the Pcdh enhancer reconfigures the topology of chromatin loops between the distal enhancer and target promoters and alters gene-expression patterns. Thus, although enhancers can function in an orientation-independent manner in reporter assays, in the native chromosome context, the orientation of at least some enhancers carrying CBSs can determine both the architecture of topological chromatin domains and enhancer/promoter specificity. These findings reveal how 3D chromosome architecture can be encoded by linear genome sequences.

引用

页码：900 / 910

页数：11

共 52 条

[1] Mechanisms of Programmed DNA Lesions and Genomic Instability in the Immune System [J].