Ectopic expression of the Stabilin2 gene triggered by an intracisternal A particle (IAP) element in DBA/2J strain of mice

• DOI: 10.1007/s00335-019-09824-1
• Publication Date: 2020-01-07T17:03:14Z
• Authors: Nobuyo Maeda-Smit...; Sylvia Hiller; Sharlene Dong; Hyung-Suk Kim; Brian J. Bennett; Yukako Kayashima
• Keywords: 0301 basic medicine; Mice, 129 Strain; Neuronal; 1.1 Normal biological development and functioning; Cell Adhesion Molecules, Neuronal; 129 Strain; Inbred C57BL; Chromosomes; Article; Ectopic Gene Expression; Promoter Regions; Mice; 03 medical and health sciences; Genetic; Underpinning research; Genetics; 2.1 Biological and endogenous factors; Inbred DBA; Animals; Humans; Aetiology; Hyaluronic Acid; Promoter Regions, Genetic; Alleles; Genetics & Heredity; Mammalian; Endothelial Cells; Genetic Variation; Intracisternal A-Particle; Biological Sciences; DNA Methylation; Chromosomes, Mammalian; Mice, Inbred C57BL; Genes, Intracisternal A-Particle; HEK293 Cells; Genes; Liver; Mice, Inbred DBA; Cell Adhesion Molecules

AbstractStabilin2(Stab2) encodes a large transmembrane protein which is predominantly expressed in the liver sinusoidal endothelial cells (LSECs) and functions as a scavenger receptor for various macromolecules including hyaluronans (HA). In DBA/2J mice, plasma HA concentration is ten times higher than in 129S6 or C57BL/6J mice, and this phenotype is genetically linked to theStab2locus.Stab2mRNA in the LSECs was significantly lower in DBA/2J than in 129S6, leading to reduced STAB2 proteins in the DBA/2J LSECs. We found a retrovirus-derived transposable element, intracisternal A particle (IAP), in the promoter region ofStab2DBAwhich likely interferes with normal expression in the LSECs. In contrast, in other tissues of DBA/2J mice, the IAP drives high ectopicStab2DBAtranscription starting within the 5′ long terminal repeat of IAP in a reverse orientation and continuing through the downstreamStab2DBA. Ectopic transcription requires theStab2-IAP element but is dominantly suppressed by the presence of loci on 59.7–73.0 Mb of chromosome (Chr) 13 from C57BL/6J, while the same region in 129S6 requires additional loci for complete suppression. Chr13:59.9–73 Mb contains a large number of genes encoding Krüppel-associated box-domain zinc-finger proteins that target transposable elements-derived sequences and repress their expression. Despite the high amount of ectopicStab2DBAtranscript in tissues other than liver, STAB2 protein was undetectable and unlikely to contribute to the plasma HA levels of DBA/2J mice. Nevertheless, the IAP insertion and its effects on the transcription of the downstreamStab2DBAexemplify that stochastic evolutional events could significantly influence susceptibility to complex but common diseases.