title: Interruption of intrachromosomal looping by CCCTC binding factor decoy proteins abrogates genomic imprinting of human insulin-like growth factor II.
abstract: Monoallelic expression of IGF2 is regulated by CCCTC binding factor (CTCF) binding to the imprinting control region (ICR) on the maternal allele, with subsequent formation of an intrachromosomal loop to the promoter region. The N-terminal domain of CTCF interacts with SUZ12, part of the polycomb repressive complex-2 (PRC2), to silence the maternal allele. We synthesized decoy CTCF proteins, fusing the CTCF deoxyribonucleic acid-binding zinc finger domain to CpG methyltransferase Sss1 or to enhanced green fluorescent protein. In normal human fibroblasts and breast cancer MCF7 cell lines, the CTCF decoy proteins bound to the unmethylated ICR and to the IGF2 promoter region but did not interact with SUZ12. EZH2, another part of PRC2, was unable to methylate histone H3-K27 in the IGF2 promoter region, resulting in reactivation of the imprinted allele. The intrachromosomal loop between the maternal ICR and the IGF2 promoters was not observed when IGF2 imprinting was lost. CTCF epigenetically governs allelic gene expression of IGF2 by orchestrating chromatin loop structures involving PRC2.
authors.affiliation: Department of Biochemistry and Molecular Biology, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: He
authors.initials: H
authors.lastname: Zhang
authors.forename: Beibei
authors.initials: B
authors.lastname: Niu
authors.forename: Ji-Fan
authors.initials: JF
authors.lastname: Hu
authors.forename: Shengfang
authors.initials: S
authors.lastname: Ge
authors.forename: Haibo
authors.initials: H
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.forename: Jianqun
authors.initials: J
authors.lastname: Ling
authors.forename: Brandon N
authors.initials: BN
authors.lastname: Steelman
authors.forename: Guanxiang
authors.initials: G
authors.lastname: Qian
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Hoffman
mesh_terms: D000483:Alleles; D000076246:CCCTC-Binding Factor; D002352:Carrier Proteins / Q000378:metabolism; D002843:Chromatin / Q000737:chemistry; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000378:metabolism; D020868:Gene Silencing; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000378:metabolism; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism*; D014157:Transcription Factors; D016335:Zinc Fingers
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D002352:Carrier Proteins; D002843:Chromatin; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; C430461:SUZ12 protein, human; D014157:Transcription Factors; D007335:Insulin-Like Growth Factor II; D063151:Polycomb Repressive Complex 2