title: A novel pathway links oxidative stress to loss of insulin growth factor-2 (IGF2) imprinting through NF-κB activation.
abstract: Genomic imprinting is the allele-specific expression of a gene based on parental origin. Loss of imprinting(LOI) of Insulin-like Growth Factor 2 (IGF2) during aging is important in tumorigenesis, yet the regulatory mechanisms driving this event are largely unknown. In this study oxidative stress, measured by increased NF-κB activity, induces LOI in both cancerous and noncancerous human prostate cells. Decreased expression of the enhancer-blocking element CCCTC-binding factor(CTCF) results in reduced binding of CTCF to the H19-ICR (imprint control region), a major factor in the allelic silencing of IGF2. This ICR then develops increased DNA methylation. Assays identify a recruitment of the canonical pathway proteins NF-κB p65 and p50 to the CTCF promoter associated with the co-repressor HDAC1 explaining gene repression. An IκBα super-repressor blocks oxidative stress-induced activation of NF-κB and IGF2 imprinting is maintained. In vivo experiments using IκBα mutant mice with continuous NF-κB activation demonstrate increased IGF2 LOI further confirming a central role for canonical NF-κB signaling. We conclude CTCF plays a central role in mediating the effects of NF-κB activation that result in altered imprinting both in vitro and in vivo. This novel finding connects inflammation found in aging prostate tissues with the altered epigenetic landscape.
authors.affiliation: Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: Bing
authors.initials: B
authors.lastname: Yang
authors.affiliation: Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wagner
authors.affiliation: Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: Nathan
authors.initials: N
authors.lastname: Damaschke
authors.affiliation: Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: Tianyu
authors.initials: T
authors.lastname: Yao
authors.affiliation: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Shelly M
authors.initials: SM
authors.lastname: Wuerzberger-Davis
authors.affiliation: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Moon-Hee
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Comparative Biosciences, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Svaren
authors.affiliation: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin, United States of America ; University of Wisconsin Carbone Comprehensive Cancer Center, Madison, Wisconsin, United States of America.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Miyamoto
authors.affiliation: Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America ; University of Wisconsin Carbone Comprehensive Cancer Center, Madison, Wisconsin, United States of America ; Environmental and Molecular Toxicology, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: David F
authors.initials: DF
authors.lastname: Jarrard
mesh_terms: D000483:Alleles; D000818:Animals; D000076246:CCCTC-Binding Factor; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D057890:Epigenomics; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D018392:Genomic Imprinting; D006801:Humans; D007249:Inflammation; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D008297:Male; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D011471:Prostatic Neoplasms / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; C000619698:Ctcf protein, mouse; C035170:IGF2 protein, human; D016328:NF-kappa B; D012097:Repressor Proteins; D007335:Insulin-Like Growth Factor II