Differential expression of related HLA class II DQ beta genes caused by nucleotide variation in transcriptional regulatory elements.
HLA class II genes comprise a large multigene family with intra- and interlocus variation in structure and expression. Within this family of related genes, the HLA-DX alpha and beta loci (HLA DQA2 and DQB2) are highly homologous to functional HLA-DQ loci (HLA DQA1 and DQB1) but are frequently termed pseudogenes because DX gene transcription has not been observed, even in cells expressing HLA-DQ. Analysis of upstream transcriptional regulatory elements for the DX beta and DQ beta genes identified a high degree of nucleotide homology, consistent with their derivation from a common ancestral class II gene. However, transient expression assays with plasmids utilizing promoter elements from the DX beta gene had no activity in transfected human B cells, in contrast to homologous DQ beta sequences. Reciprocal exchange of specific sequences from the DQ beta gene with those of the DX beta gene restored expression to wild-type DQ beta levels, as did mutagenesis of only three DX-specific nucleotides in the upstream regulatory region. These three nucleotides mark two binding sites for distinct nuclear DNA-binding proteins that differentially recognize DQ beta and DX beta sequences. Transcription of these genes is critically dependent on interactions between these two upstream regulatory region sites which distinguish DX beta from its closely related homologue, DQ beta.
Shewey
L M
LM
Virginia Mason Research Center, Seattle, WA 98101.
Beaty
J S
JS
Andersen
L C
LC
Nepom
G T
GT
D001483:Base Sequence; D015500:Chloramphenicol O-Acetyltransferase / Q000032:analysis / Q000235:genetics; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation; D006683:HLA-DQ Antigens / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D014158:Transcription, Genetic
D006683:HLA-DQ Antigens; D009687:Nuclear Proteins; D004247:DNA; D015500:Chloramphenicol O-Acetyltransferase