Intragenic transcriptional interference regulates the human immune ligand MICA

Abstract

Many human genes have tandem promoters driving overlappingtranscription, but the value of this distributed promoter configura-tion is generally unclear. Here we show thatMICA, a gene encodinga ligand for the activating immune receptor NKG2D, contains aconserved upstream promoter that expresses a noncoding tran-script. Transcription from the upstream promoter represses thedownstream standard promoter activity incisthrough transcrip-tional interference. The effect of transcriptional interferencedepends on the strength of transcription from the upstreampromoter and can be described quantitatively by a simple recipro-cal repressor function. Transcriptional interference coincides withrecruitment at the standard downstream promoter of the FACThistone chaperone complex, which is involved in nucleosomalremodelling during transcription. The mechanism is invoked in theregulation of MICA expression by the physiological inputs inter-feron-cand interleukin-4that act on the upstream promoter.Genome-wide analysis indicates that transcriptional interferencebetween tandem intragenic promoters may constitute a generalmechanism with widespread importance in human transcriptionalregulation