Repetitive Elements in the 5′ Untranslated Region of a Human Zinc-Finger Gene Modulate Transcription and Translation Efficiency

Abstract

A substantial proportion of the human genome consists of repetitive sequences. Although most of these sequences are nonessential for the organism, retroelements, such as Alu sequences, L1s, and HERVs (human endogenous retroviruses), have recently been implicated in the regulation of various genes. Our laboratory previously identified a novel, alternatively spliced zinc-finger gene, ZNF177, which incorporates Alu L1, and HERV segments into the 5′ untranslated region (UTR) of transcripts. In this study, we investigated the genomic structure and functional significance of the repetitive sequences in the 5′ UTR of ZNF177 mRNAs. Using luciferase and GFP reporter constructs, we assessed the effect of the HERV, Alu, and L1 sequences on gene expression levels. Our results indicate that the presence of the retroelement sequences, particularly the Alu and L1 segments which form one 5′ UTR exon, modifies the expression level of both reporter genes. We present evidence that the Alu and L1 sequences alter both the RNA and protein levels of reporter genes by increasing transcription efficiency while decreasing translation efficiency. Our findings indicate that the Alu and L1 repeats in the 5′ UTR of ZNF177 exert a positive transcriptional enhancer effect, but repress translation of the zinc finger gene. In addition, our analysis of a 5′ UTR database suggests that 4% of human 5′ UTRs harbor Alu sequences, indicating that the expression of many genes might be influenced by Alu repeats. These results illustrate the complex regulatory effects that retroelements can have on human gene expression.