Developmental regulation of MHC Class I gene expression has been studied in vitro with F9 embryonal teratocarcinoma (EC) cells. Undifferentiated F9 EC cells do not express the MHC antigens, while these cells treated with retinoic acid, or interferons, accumulate both MHC Class I mRNA and the MHC Class I antigens. We have constructed chloramphenicol acetyl transferase (CAT) genes connected to various portions of the 5' flanking region of a mouse MHC Class I gene in F9 EC cells. We found that the upsteam sequence of the MHC Class I antigen contains a sequence which represses the promoter activity of the gene in undifferentiated F9 cells. The repression was no longer found when F9 EC cells are differentiated with retinoic acid. Studies of constructs containing internal deletions allowed us to map the sequence controlling the repression to -130 to -210 bp upstream from the cap site. When a fragment containing this """"""""regulatory sequence"""""""" was placed in the upstream of a SV40 promoter, the characteristic repression of the CAT activity was observed in undifferentiated F9 EC cells. This repression was relieved upon differentiation of the EC cells. We postulate that developmental regulation of MHC Class I genes is controlled, in part, by this regulatory sequence. In a separate study, we found that interferons (IFNs) induce proto-oncogene c-fos in a variety of tissue culture cells. The induction of c-fos mRNA is rapid and transient occurring within 15 minutes of IFN treatment; the elevated levels return to basal levels within 2 hours. c-fos and Class I mRNA are thus induced in a sequential manner by IFN treatment in tissue cultures. Moreover, c-fos is found to be transiently expressed in several tissues during murine neonatal development. Sharp increases in the level of MHC Class I mRNA occur immediately following this event, suggesting that IFNs may play a role in postnatal mammalian development.
