A novel pathway links oxidative stress to loss of Insulin Growth Factor-2 (IGF2) imprinting through NF-κB activation

Bing Yang, Jennifer Wagner, Nathan Damaschke, Tianyu Yao, Shelly M. Wuerzberger-Davis, Moon Hee Lee, John Svaren, Shigeki Miyamoto, David F. Jarrard

Research output: Contribution to journalArticle

20 Scopus citations

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.

Original languageEnglish (US)
Article numbere88052
JournalPloS one
Volume9
Issue number2
DOIs
StatePublished - Feb 18 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Yang, B., Wagner, J., Damaschke, N., Yao, T., Wuerzberger-Davis, S. M., Lee, M. H., Svaren, J., Miyamoto, S., & Jarrard, D. F. (2014). A novel pathway links oxidative stress to loss of Insulin Growth Factor-2 (IGF2) imprinting through NF-κB activation. PloS one, 9(2), [e88052]. https://doi.org/10.1371/journal.pone.0088052