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PLoS One. 2014 Feb 18;9(2):e88052. doi: 10.1371/journal.pone.0088052. eCollection 2014.

A novel pathway links oxidative stress to loss of insulin growth factor-2 (IGF2) imprinting through NF-κB activation.

Author information

1
Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
2
Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin, United States of America.
3
Comparative Biosciences, University of Wisconsin, Madison, Wisconsin, United States of America.
4
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.
5
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.

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.

PMID:
24558376
PMCID:
PMC3928145
DOI:
10.1371/journal.pone.0088052
[Indexed for MEDLINE]
Free PMC Article
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