Relationships between Deficits in Tissue Mass and Transcriptional Programs after Partial Hepatectomy in Mice

Liver regeneration after two-thirds partial hepatectomy (2/3 PH) results in synchronized proliferation of hepatocytes and rapid restoration of liver mass. Understanding the mechanisms that regulate this process has both biological and clinical importance. Using cDNA microarray analysis, we investigated whether gene activation after 2/3 PH is specifically related to liver growth and hepatocyte proliferation. We generated gene expression profiles at 4, 12, 20, and 30 hours after 2/3 PH and compared them with profiles obtained at the same time points after 1/3 PH, a procedure that causes minimal DNA replication. Surprisingly, a significant number of genes whose expression is altered after 2/3 PH are similarly up- or down-regulated after 1/3 PH, particularly at 4 hours. We identified a number of genes and transcription factors that are more highly expressed (preferential expression) after 2/3 PH and show that a shift in transcriptional programs in the regenerating liver occurs between 4 and 12 hours after 2/3 PH, a time at which the decision to replicate appears to be made. These results show that the liver responds to PH with massive changes of gene expression, even in the absence of DNA replication. We suggest that the changes in gene expression during the first 4 to 6 hours after 2/3 PH may induce chromatin remodeling and facilitate the binding of new sets of transcription factors required for DNA replication. (Am J Pathol 2009, 175:947-957; DOP 10.2353/ajpath.2009.090043)