Cohesin Is Required for Higher-Order Chromatin Conformation at the Imprinted IGF2-H19 Locus

被引:263
作者
Nativio, Raffaella [1 ]
Wendt, Kerstin S. [3 ]
Ito, Yoko [1 ]
Huddleston, Joanna E. [1 ]
Uribe-Lewis, Santiago [1 ]
Woodfine, Kathryn [1 ]
Krueger, Christel [2 ]
Reik, Wolf [2 ,4 ]
Peters, Jan-Michael [3 ]
Murrell, Adele [1 ]
机构
[1] Univ Cambridge, Canc Res UK, Cambridge Res Inst, Dept Oncol, Cambridge, England
[2] Babraham Inst, Lab Dev Genet & Imprinting, Cambridge, England
[3] Inst Mol Pathol, A-1030 Vienna, Austria
[4] Univ Cambridge, Ctr Trophoblast Res, Cambridge, England
来源
PLOS GENETICS | 2009年 / 5卷 / 11期
基金
英国生物技术与生命科学研究理事会; 奥地利科学基金会;
关键词
DE-LANGE-SYNDROME; DIFFERENTIALLY METHYLATED REGIONS; GROWTH-FACTOR-II; GENE-EXPRESSION; CTCF-BINDING; NIPPED-B; COLORECTAL-CANCER; IGF2/H19; DOMAIN; H19/IGF2; LOCUS; OVARIAN-CANCER;
D O I
10.1371/journal.pgen.1000739
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Cohesin is a chromatin-associated protein complex that mediates sister chromatid cohesion by connecting replicated DNA molecules. Cohesin also has important roles in gene regulation, but the mechanistic basis of this function is poorly understood. In mammalian genomes, cohesin co-localizes with CCCTC binding factor (CTCF), a zinc finger protein implicated in multiple gene regulatory events. At the imprinted IGF2-H19 locus, CTCF plays an important role in organizing allele-specific higher-order chromatin conformation and functions as an enhancer blocking transcriptional insulator. Here we have used chromosome conformation capture (3C) assays and RNAi-mediated depletion of cohesin to address whether cohesin affects higher order chromatin conformation at the IGF2-H19 locus in human cells. Our data show that cohesin has a critical role in maintaining CTCF-mediated chromatin conformation at the locus and that disruption of this conformation coincides with changes in IGF2 expression. We show that the cohesin-dependent, higher-order chromatin conformation of the locus exists in both G1 and G2 phases of the cell cycle and is therefore independent of cohesin's function in sister chromatid cohesion. We propose that cohesin can mediate interactions between DNA molecules in cis to insulate genes through the formation of chromatin loops, analogous to the cohesin mediated interaction with sister chromatids in trans to establish cohesion.
引用
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页数:15
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