Genome‐wide combinatorial transcriptional regulatory dynamics during early onset of liver regeneration and chronic alcohol intake

Abstract

The objective of this study is to characterize effects of chronic alcohol consumption on genome‐scale transcriptional regulatory network dynamics during the early phase liver regeneration after 70% partial hepatectomy (PHx) at 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 an isocaloric liquid diet with carbohydrate replacing ethanol. Genome‐wide binding targets for NF‐kB, C/EBPbeta, and STAT3 were detected either by Roche NimbleGen ChIP‐chip or ABI SOLID sequencing approach. Our results indicate significant differences in the binding profiles of all the three regulators in chronic ethanol compared to isocaloric controls, at baseline as well as in response to PHx. Pathway analysis revealed that potential target genes specific to the chronic ethanol group participate in key processes such as mitochondria processing, DNA methylation, cell death, proteolysis, histone modification, lipid biosynthetic process, and regulation of cell cycle. Our results provide a first system‐wide view of the regulatory network dynamics in liver regeneration as it is affected by alcohol, and implicate combinatorial regulatory modules as participating in the adverse liver regeneration response. Research Support: NIH AA018873 and AA017261.