Identification of bidirectional promoters in the human KIR genes

Abstract

Although the class I MHC receptors expressed by human and mouse natural killer (NK) cells have distinct molecular origins, they are functional analogues that are expressed in a variegated pattern. The murine Ly49 class I receptors contain bidirectional promoters that have been proposed to control the probabilistic expression of these genes. Whether similar elements are present in the human killer Ig-like receptor (KIR) genes is a fundamental question. A detailed analysis of the 2 kb intergenic region separating the KIR2DL4 gene and the adjacent KIR3DL1 gene revealed that additional promoter elements exist in the human KIR genes. Remarkably, the previously characterized KIR3DL1 proximal promoter possesses bidirectional promoter activity that maps to an 88 bp DNA fragment containing CREB, AML, Sp1 and Ets transcription factor binding sites. Individual KIR genes and alleles possess bidirectional promoters with distinct properties. Analysis of KIR þ and KIR À NK cells and NK precursors indicates that reverse transcripts from the bidirectional promoter are found in cells that lack KIR protein expression, but are not present in mature KIR-expressing NK cells, suggesting that reverse transcription from the proximal promoter blocks gene activation in immature NK and precursor cells.

Divergent transcription: A new feature of active promoters

“…Activation of members of the KIR and Ly49 family of receptor genes in human and mice, respectively, is thought to be controlled by the relative strength of a competing promoter that directs divergent transcription upstream of the promoters. 66,67 A similar type of competition has been observed at the yeast TPL1 gene, where a mutation in the TATA box enhances anti-sense transcription from this promoter. 1…”

KIR acquisition probabilities are independent of self-HLA class I ligands and increase with cellular KIR expression

“…37 These models imply that intergenic RNAs produced via probabilistic mechanisms control the selective activation or silencing of KIR alleles. 37,38 Moreover, polymorphism in transcription factor binding sites was recently shown to affect the functional activity of bidirectional KIR promoters that are associated with distinct frequencies of receptor expression. 39 Future experiments in which KIR promoter polymorphism is studied in donors with the 3 distinct KIR repertoires may provide a molecular explanation for the set points of KIR acquisition probabilities.…”

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…High CpG methylation of the KIR proximal promoter was reported in NK cells and CD8 + T cells lacking expression of the corresponding KIR molecule, and vice versa 139, 140, 141. KIR expression requires the intermediate promoter Pro1;142 however, the strength of KIR proximal promoter antisense activity is probably responsible for clonal KIR distribution in NK and T cells 7, 142, 143, 144. The relative affinity of binding sites for transcription factors involved in sense versus antisense promoter activity determines the probability of generating the sense transcript required for gene activation 142, 143.…”

“…KIR expression requires the intermediate promoter Pro1;142 however, the strength of KIR proximal promoter antisense activity is probably responsible for clonal KIR distribution in NK and T cells 7, 142, 143, 144. The relative affinity of binding sites for transcription factors involved in sense versus antisense promoter activity determines the probability of generating the sense transcript required for gene activation 142, 143. A recent mouse study suggests that activating receptor‐mediated signalling might regulate this process during NK cell development 145.…”