Transcriptional control in hepatocytes of normal and c14CoS albino deletion mice.

The transcription rates of the albumin and alpha-fetoprotein (alpha FP) genes were reduced to marginally detectable levels in livers of newborn or fetal c14CoS albino deletion mutant mice, which lack the hepatocyte specific developmental regulation (hsdr-1) locus on chromosome 7 and die shortly after birth. However, steady-state levels of these two mRNAs in livers of mutant mice were similar to those in normal mice, where these genes are actively transcribed. In c14CoS mice, transcription rates of transcription factor genes HNF-1, C/EBP and HNF-4 were reduced, albeit to different extents. These effects are specific because transcription of the HNF-3, DBP, LAP and Jun-B genes remained normal in mutant mice. Steady-state levels of all of these mRNAs reflected the transcriptional activities. Levels of HNF-1 and HNF-4 mRNAs showed much greater depression than that of C/EBP in mutant liver. The availability of this group of transcription factors may be reduced in c14CoS hepatocytes and therefore caused depressed transcription rates of their target genes such as those encoding albumin and alpha FP. However, the normal steady-state levels of albumin and alpha FP mRNAs in mutant mice remains unexplained. Fetal c14CoS hepatocytes in primary culture did acquire competence for glucocorticoid inducible transcription of the albumin, alpha FP, HNF-4 and metallothionein genes but not of the tyrosine aminotransferase (TAT) gene. These results indicate that the hsdr-1 locus is dispensable for the glucocorticoid induced transcription of these genes but not of TAT. The effects caused by the c14CoS deletion are pleiotropic in controlling the expression of numerous genes at distinct levels in the liver.