Alternative 5’ Untranslated Regions Are Involved in Expression Regulation of Human Heme Oxygenase-1

Abstract

The single nucleotide polymorphism rs2071746 and a (GT)n microsatellite within the human gene encoding heme oxygenase-1 (HMOX1) are associated with incidence or outcome in a variety of diseases. Most of these associations involve either release of heme or oxidative stress. Both polymorphisms are localized in the promoter region, but previously reported correlations with heme oxygenase-1 expression remain not coherent. This ambiguity suggests a more complex organization of the 5’ gene region which we sought to investigate more fully.We evaluated the 5‘ end of HMOX1 and found a novel first exon 1a placing the two previously reported polymorphisms in intronic or exonic positions within the 5’ untranslated region respectively. Expression of exon 1a can be induced in HepG2 hepatoma cells by hemin and is a repressor of heme oxygenase-1 translation as shown by luciferase reporter assays. Moreover, minigene approaches revealed that the quantitative outcome of alternative splicing within the 5’ untranslated region is affected by the (GT)n microsatellite.This data supporting an extended HMOX1 gene model and provide further insights into expression regulation of heme oxygenase-1. Alternative splicing within the HMOX1 5' untranslated region contributes to translational regulation and is a mechanistic feature involved in the interplay between genetic variations, heme oxygenase-1 expression and disease outcome.

Identification of promoter polymorphisms in the cytochrome P450 CYP6AY1 linked with insecticide resistance in the brown planthopper, Nilaparvata lugens

“…The 5′RACE results demonstrated the presence of CYP6AY1 alternative splice products in the 5′-UTR. Studies on human surfactant protein (SFTPA1/2) and heme oxygenase-1 have demonstrated that alternative splicing of the 5′-UTR can impact mRNA stability and translation efficiency (Wang et al, 2005;Kramer et al, 2013). In addition, at least five alternative splicings in the 5′-UTR of the P450 gene CYP19B1 have been found in rainbow trout, which may be involved in the developmental regulation of this gene or to the control of distinct gonadal cell types (von Schalburg et al, 2010).…”

Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation

“…151 Microsatellite polymorphisms can affect alternative splicing in the HMOX1 5′ untranslated region, thus providing an additional regulatory mechanism for HMOX1 translation. 152 Additional SNPs in HMOX1 have been identified, including rs2071746 T/A which has been associated with increased risk of Parkinson’s disease, and with protection from cardiovascular disease. 153–154 …”

Link Between Short tandem Repeats and Translation Initiation Site Selection

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