Chronic alcohol effects on NF‐κB genome‐wide binding dynamics during early onset of liver regeneration

Abstract

The objective of this study is to characterize effects of chronic alcohol consumption on NF‐κB mediated transcriptional regulatory network dynamics during the early phase liver regeneration after 70% partial hepatectomy (PHx) at 1 and 6h post 2/3rd PHx in the rat. Rats were fed liquid diet containing 36% of total calories derived from ethanol for 5 weeks, controls were pair‐fed isocaloric liquid diet. Genome‐wide NF‐κB binding targets were detected using Roche NimbleGen ChIP‐chip microarray platform using Chromatin Immunoprecipitated (ChIP) samples, several of which were validated by ChIP‐qPCR. Our results indicate that (1) chronic ethanol diet did not increase the genome‐wide binding activity of NF‐κB at the baseline state with ~3200 target gene promoters; (2) PHx induced significant increase in NF‐κB genome‐wide binding at 1h, more so in chronic ethanol samples (5300 genes) than in controls (4000 genes). At 6h post PHx, only the control samples showed a further increase in NF‐κB promoter binding ~5500 genes. Pathway analysis revealed that NF‐κB target genes specific to the chronic ethanol group participate in key processes such as DNA methylation, cell death, proteolysis, histone modification and regulation of cell cycle. We conclude that at least some of the chronic ethanol effects on liver regeneration are mediated by altered NF‐κB binding at specific pathway genes. Research Support: NIH AA018873, AA016919.