Interferon-A (IFN-A) differential gene expression is modulated by a co
mplex interplay between cis-acting DNA elements and the corresponding
specific trans-regulating factors, Substitutions in the proximal virus
-responsive element of the interferon-A (IFN-A) promoters contribute t
o their differential gene expression, The 5' distal silencing region i
n the weakly virus-inducible murine IFN-A11 gene has been previously d
elimited. DNase I footprinting experiments and transient gene expressi
on assays demonstrate identical silencing activity in equivalent regio
ns of the genes for IFN-A11 and IFN-A4 promoters. A minimal 20-mer dis
tal negative regulatory element (DNRE) in both promoters is necessary
and sufficient for the silencing and a region in the highly inducible
IFN-A4 promoter located between the silencer and the virus-responsive
element overrides the silencer activity. Mutations in the central regi
on of the DNRE, causing derepression, also altered the formation of on
e of the two major DNA-protein complexes, One of these contains a prot
ein related to or identical to the high mobility group I(Y) proteins,
while the other complex contains a major protein present in uninduced
and virus-induced cells with a molecular mass of 38 kDa, which may be
related to the silencer activity. Similar DNREs are present in other v
irus-uninducible IFN-A promoters, and these data suggest that a common
silencer may mediate the transcriptional repression in different gene
s of this family.