Characterization of a weakly expressed KIR2DL1 allele supports a positive role for the KIR distal promoter in proximal KIR promoter activation. (P1357)

Abstract

Abstract The variegated expression of the human KIR family of class I MHC receptors provides an interesting model system for the study of stochastic activation of gene transcription. Previous studies have linked distal KIR promoter transcription to the initiation of KIR expression from the proximal promoter. In order to identify novel genetic alterations associated with decreased KIR expression, a group of 182 donors was characterized for KIR gene content, KIR transcripts, and FACS analysis of KIR surface expression. An individual was discovered that possessed a single copy of the KIR2DL1 gene but had a low level of gene expression by either FACS or Q-PCR. Complete sequencing of the KIR2DL1 gene confirmed the presence of an intact coding region. Analysis of the three known promoter regions revealed a cluster of 3 single nucleotide polymorphisms (SNPs) in the distal promoter region approximately 1 kb upstream from the start of KIR2DL1 translation. These SNPs are also found in the distal promoter region of the non-transcribed KIR2DL5*002 allele as well as the KIR3DP1 pseudogene. One of these SNPs creates a binding site for the inhibitory ZEB1 transcription factor that overlaps a c-Myc binding site previously implicated in the activation of KIR genes by distal transcription. We therefore propose that the generation of this novel ZEB1-binding site antagonizes the Myc-associated activation of the KIR2DL1 gene by the distal promoter.