Transcriptional activation of the rat liver S14 gene during postnatal development

The mRNA coding for the rat liver S14 protein (Mr 17,000, pI 4.9) shows profound increases during postnatal development. In an effort to define the molecular basis for the postnatal rise in mRNAs14 we examined the chromatin organization of the S14 gene, its DNA methylation state, the hepatic expression of mRNAs14, and the in vitro S14 "run-on" activity prior to and after weaning at 21 days postpartum. In animals less than or equal to 15 days of age, the hepatic S14 gene is transcriptionally inactive, mRNAs14 levels are less than or equal to 0.5% of adult levels, and the chromatin organization within 11 kilobases of the 5' end of the S14 gene is similar to that found in tissues not expressing mRNAs14. From 18 to 22 days postpartum, the transcriptional activity of the S14 gene increases greater than or equal to 40-fold and mRNAs14 increases greater than or equal to 100-fold approaching adult levels of expression. Highly specific changes in S14 chromatin structure accompany gene activation. The formation of Hss-1 near the S14 cap site (-65 to -265 base pairs) and Hss-3 -3.3 kilobases upstream from the S14 cap site suggests that changes in DNA-protein interaction at these sites may function in both the tissue-specific and developmental regulation of S14 gene expression. The methylation studies suggest HhaI sites may be a cue for the tissue-specific expression of S14. However, the maintenance of hypermethylated HpaII sites throughout S14 gene activation argues against a role for these sites in either the tissue-specific or developmental regulation of S14 gene expression. These studies show that the principal molecular mechanism accounting for the major rise in mRNAs14 during postnatal development is activation of gene transcription and not stabilization of S14 RNA.