Are the KIR genes actively silenced prior to their tissue‐specific activation? A KIR intronic promoter produces spliced antisense transcripts in human ES cells

Abstract

The KIR genes are in a silent methylated state in NK progenitors prior to their selective activation by developing NK cells. We have recently identified an additional antisense transcript originating in the second KIR intron. The KIR2DL1 antisense transcript is composed of three exons that contain: (1) a segment from intron 2; (2) exon 2 plus flanking intron sequences; (3) exon 1 plus the bidirectional promoter region. The composition of the spliced antisense KIR transcript (KIRaS) suggests that it functions to silence KIR gene expression. KIRaS was detected in human embryonic stem (ES) cells, an embryonal carcinoma (EC) cell line (Ntera2), and the HEK293 cell line, but not NK, T, or B cell lines. In vitro promoter analysis revealed that KIRaS promoter activity is only detected in the cell lines where transcript is present. Promoter activity is controlled by the MZF‐1 transcription factor that is expressed in totipotent hematopoieticcells and myeloid progenitors. KIR gene activation appears to be under the control of four distinct promoter units: distal forward; proximal forward or reverse; distal antisense. The potential interplay of the multiple KIR promoters and the timing of their expression during development will be discussed.Funded by NCI Contract N01‐CO‐12400