A novel, dynamic pattern-based analysis of NF-?B binding during the priming phase of liver regeneration reveals switch-like functional regulation of target genes.
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ABSTRACT: Following partial hepatectomy, a coordinated series of molecular events occurs to regulate hepatocyte entry into the cell cycle to recover lost mass. In rats during the first 6 h following resection, hepatocytes are primed by a tightly controlled cytokine response to prepare hepatocytes to begin replication. Although it appears to be a critical element driving regeneration, the cytokine response to resection has not yet been fully characterized. Specifically, the role of one of the key response elements to cytokine signaling (NF-?B) remains incompletely characterized. In this study, we present a novel, genome-wide, pattern-based analysis characterizing NF-?B binding during the priming phase of liver regeneration. We interrogated the dynamic regulation of priming by NF-?B through categorizing NF-?B binding in different temporal profiles: immediate sustained response, early transient response, and delayed response to partial hepatectomy. We then identified functional regulation of NF-?B binding by relating the temporal response profile to differential gene expression. We found that NF-?B bound genes govern negative regulation of cell growth and inflammatory response immediately following hepatectomy. NF-?B also transiently regulates genes responsible for lipid biosynthesis and transport as well as induction of apoptosis following hepatectomy. By the end of the priming phase, NF-?B regulation of genes involved in inflammatory response, negative regulation of cell death, and extracellular structure organization became prominent. These results suggest that NF-?B regulates target genes through binding and unbinding in immediate, transient, and delayed patterns. Such dynamic switch-like patterns of NF-?B binding may govern different functional transitions that drive the onset of regeneration.
SUBMITTER: Cook DJ
PROVIDER: S-EPMC4493398 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
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