Adaptation to chronic alcohol intake alters STAT3 genome‐wide binding dynamics during liver regeneration

Abstract

The objective of this study is to characterize effects of adaptation to chronic alcohol intake on STAT3 mediated transcriptional regulatory networks during the priming phase of liver regeneration. Rats were fed liquid diet containing 36% of total calories derived from ethanol for 5 weeks, and control animals were pair‐fed an isocaloric liquid diet. A 70% partial hepatectomy (PHx) was performed. Genome‐wide STAT3 binding targets were detected by ABI SOLiD sequencing of Chromatin Immunoprecipitated (ChIP) samples. Our results indicate that (1) STAT3 targets 114 promoters in control samples, and 794 promoters in chronic ethanol at the baseline adapted state; (2) PHx induced a significant increase in STAT3 binding at 6h, in chronic ethanol samples (771 genes) versus controls (246 genes). STAT3 target genes specific to the chronic ethanol group participate in key processes such as protein complex assembly, cell signaling, RNA metabolic process, and programmed cell death etc. Based on identified STAT3 motifs in target promoters, we found combinatorial interaction between multiple transcription factors. We conclude that chronic ethanol effects on liver regeneration are mediated by altered STAT3 binding at specific pathway genes. Research Support: NIH R01 AA018873, K05 AA017261, and T32 AA007463.