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

Authors: MAEDA-SMITHIES, NOBUYO - University Of North Carolina; HILLER, SYLVIA - University Of North Carolina; DONG, SHARLENE - University Of North Carolina; SUK KIM, HYUNG - University Of North Carolina; Bennett, Brian; KAYASHIMA, YUKAKO - University Of North Carolina

Submitted to: Mammalian Genome
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/29/2019
Publication Date: 1/7/2020
Citation: Maeda-Smithies, N., Hiller, S., Dong, S., Suk Kim, H., Bennett, B.J., Kayashima, Y. 2020. Ectopic expression of the Stabilin2 gene triggered by an intracisternal A particle (IAP) element in DBA/2J strain of mice. Mammalian Genome. 31:2-16. https://doi.org/10.1007/s00335-019-09824-1.
DOI: https://doi.org/10.1007/s00335-019-09824-1

Interpretive Summary: As the power of the high-throughput sequencing technique evolves, information on genomic variations between species, strains and individuals is rapidly accumulating. However, the biological effects of each variation and the interactions among those variants, which can cause differences in physiological traits and nutritional need, have not been fully understood. Inherited alterations in genomic sequence take a variety of forms including retrovirus-derived transposable elements. In this manuscript we identify and characterize a specific transposable element which affects the expression of a gene named Stabilin2 (Stab2). We previously identified this gene as a candidate gene affecting aortic arch atherosclerosis. These studies clarify the molecular mechanism underlying the ectopic expression of this gene.

Technical Abstract: Stabilin2 (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 10 times higher than in 129S6 mice, and this phenotype is genetically linked to the Stab2 locus. Stab2 mRNA in the LSECs was significantly lower in DBA/2J than in 129S6, leading to a reduced STAB2 proteins in the DBA/2J LSECs. We found a retrovirus-derived transposable element, intracisternal A particle (IAP), in the promoter region of Stab2DBA which likely interferes with normal expression in the LSECs. In contrast, in other tissues of DBA/2J mice, the IAP drives high ectopic Stab2DBA transcription starting within the 5’LTR of IAP in a reverse orientation and continues through the downstream Stab2DBA. Ectopic transcription requires the Stab2-IAP element but is dominantly suppressed by the presence of loci on 59.7-73.0Mb of chromosome (Chr) 13 from C57BL/6J, while the same region in 129S6 requires additional loci for complete suppression. Chr13:59.9-73Mb contains a large number of genes encoding Krüppel-associated box-domain zinc-finger proteins (KRAB-Zfp) that target transposable elements-derived sequences and repress their expression. Despite the high amount of ectopic Stab2DBA transcripts, STAB2 protein in the ectopic tissues 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 downstream Stab2DBA exemplify a stochastic nature of the inheritance of gene expression, which could significantly influence susceptibility to complex but common diseases.