ALTERATIONS IN MESSENGER-RNA STABILITY DURING RAT-LIVER REGENERATION

We examined the in vivo transcriptional and posttranscriptional regula tion of various genes involved in hepatocyte growth and replication th at exhibited changes in steady-state mRNA levels after 70% partial hep atectomy (PH). Of the 19 genes examined by nuclear run-on assay, 17 de monstrated no change in transcriptional activity through the first 96 h of regeneration. However, results from in vivo half-life determinati ons indicated that changes in mRNA stability played a critical role in regulating transcript levels during liver regeneration. For many of t he genes, alterations in transcript abundance correlated with similar changes in mRNA half-Lives. Inhibition of protein synthesis by cyclohe ximide was generally associated with increased levels of mRNA expressi on, but no detectable changes in transcriptional rates in both control and regenerating rat Liver. Finally, genomic methylation status was i nvestigated by Southern analysis for several genes that displayed chan ges in mRNA stability. Interestingly, increases in mRNA half-lives for the genes p53, c-myc, H-ras, and ornithine decarboxylase were associa ted with decreased genomic methylation. In conclusion, regulation of g ene expression beyond the immediate early phase of the cell cycle duri ng rat liver regeneration after PH occurs predominantly at the posttra nscriptional level. mRNA stability appears to be a significant factor in this control, and may itself be modulated by the methylation status of the corresponding genomic DNA.