Regulation of class I genes by interferons

Abstract

Major histocompatibility (MHC) class I gene expression is increased in response to interferons. In order to identify critical regulatory regions in mouse MHC (H-2) class I genes, the 5' flanking region and the DNA downstream of the transcription initiation site were analyzed separately. The promoters of H-2Dd and H-2Ld were linked to the reporter gene chloramphenicol acetyl transferase (CAT). Conversely, the H-2Ld structural gene was linked to non-interferon regulated promoters. These constructs were transfected into several different cell lines, and their ability to respond to interferons was assessed. Both regions, 5' and 3' of the transcriptional initiation site, were able to independently contribute to the regulation of class I genes by interferons. The basal levels of expression, interferon inducibility. and the relative contributions of the 3' and 5' responses to overall interferon regulation, were cell-type dependent. Sequence analysis of the 5' flanking region of class I genes led to the identification of multiple DNA motifs that are highly homologous to regulatory elements found in other genes. The H-2Dd promoter contains a TATA bog, CAAT elements, enhancer regions, and an interferon consensus sequence that is found in the promoters of many genes that are regulated by interferons. Deletion analysis and expression studies of the H-2Dd promoter revealed several interesting regulatory features of the interferon consensus sequence. It was required for both type I (alpha and beta) and type II interferon (gamma) responses. In some cell types an additional sequence was required for a type I interferon response; this sequence is located 5' and adjacent to the interferon consensus sequence. Type II interferon action was independent of this upstream sequence in all cell-types tested. Therefore the promoter controlled response to interferons is complex and the nature of the response depends both on the type of interferon and the cell-type being tested. We have noted that an interferon consensus sequence homology exists in the promoters of interferon genes. As interferons have a capacity to be auto-regulatory, we propose a model of gene regulation by interferons that incorporates what our studies and others have shown about the regulation of class I genes by interferon, and what is known about the regulation of interferon genes themselves.