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

17 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Oxidative stress
genomic imprinting
growth factors
Intercellular Signaling Peptides and Proteins
Oxidative Stress
oxidative stress
insulin
Chemical activation
Insulin
Prostate
Genes
Aging of materials
Genomic Imprinting
Co-Repressor Proteins
Somatomedins
DNA Methylation
Epigenomics
Assays
Carcinogenesis
Alleles

ASJC Scopus subject areas

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

Cite this

A novel pathway links oxidative stress to loss of Insulin Growth Factor-2 (IGF2) imprinting through NF-κB activation. / Yang, Bing; Wagner, Jennifer; Damaschke, Nathan; Yao, Tianyu; Wuerzberger-Davis, Shelly M.; Lee, Moon Hee; Svaren, John; Miyamoto, Shigeki; Jarrard, David F.

In: PloS one, Vol. 9, No. 2, e88052, 18.02.2014.

Research output: Contribution to journalArticle

Yang, B, Wagner, J, Damaschke, N, Yao, T, Wuerzberger-Davis, SM, Lee, MH, Svaren, J, Miyamoto, S & Jarrard, DF 2014, 'A novel pathway links oxidative stress to loss of Insulin Growth Factor-2 (IGF2) imprinting through NF-κB activation', PloS one, vol. 9, no. 2, e88052. https://doi.org/10.1371/journal.pone.0088052
Yang, Bing ; Wagner, Jennifer ; Damaschke, Nathan ; Yao, Tianyu ; Wuerzberger-Davis, Shelly M. ; Lee, Moon Hee ; Svaren, John ; Miyamoto, Shigeki ; Jarrard, David F. / A novel pathway links oxidative stress to loss of Insulin Growth Factor-2 (IGF2) imprinting through NF-κB activation. In: PloS one. 2014 ; Vol. 9, No. 2.
@article{6904142b22674a70ad14084cf524685d,
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.",
author = "Bing Yang and Jennifer Wagner and Nathan Damaschke and Tianyu Yao and Wuerzberger-Davis, {Shelly M.} and Lee, {Moon Hee} and John Svaren and Shigeki Miyamoto and Jarrard, {David F.}",
year = "2014",
month = "2",
day = "18",
doi = "10.1371/journal.pone.0088052",
language = "English (US)",
volume = "9",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "2",

}

TY - JOUR

T1 - A novel pathway links oxidative stress to loss of Insulin Growth Factor-2 (IGF2) imprinting through NF-κB activation

AU - Yang, Bing

AU - Wagner, Jennifer

AU - Damaschke, Nathan

AU - Yao, Tianyu

AU - Wuerzberger-Davis, Shelly M.

AU - Lee, Moon Hee

AU - Svaren, John

AU - Miyamoto, Shigeki

AU - Jarrard, David F.

PY - 2014/2/18

Y1 - 2014/2/18

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84895875887&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84895875887&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0088052

DO - 10.1371/journal.pone.0088052

M3 - Article

C2 - 24558376

AN - SCOPUS:84895875887

VL - 9

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 2

M1 - e88052

ER -