| First Author | Yang B | Year | 2014 |
| Journal | PLoS One | Volume | 9 |
| Issue | 2 | Pages | e88052 |
| PubMed ID | 24558376 | Mgi Jnum | J:213352 |
| Mgi Id | MGI:5584223 | Doi | 10.1371/journal.pone.0088052 |
| Citation | Yang B, et al. (2014) A novel pathway links oxidative stress to loss of insulin growth factor-2 (IGF2) imprinting through NF-kappaB activation. PLoS One 9(2):e88052 |
| abstractText | 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-kappaB 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-kappaB p65 and p50 to the CTCF promoter associated with the co-repressor HDAC1 explaining gene repression. An IkappaBalpha super-repressor blocks oxidative stress-induced activation of NF-kappaB and IGF2 imprinting is maintained. In vivo experiments using IkappaBalpha mutant mice with continuous NF-kappaB activation demonstrate increased IGF2 LOI further confirming a central role for canonical NF-kappaB signaling. We conclude CTCF plays a central role in mediating the effects of NF-kappaB 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. |
