Positional cloning reveals strain-dependent expression of Trim16 to alter susceptibility to bleomycin-induced...

Area of Science:

• Genetics
• Immunology
• Pulmonology

Background:

• Pulmonary fibrosis is a debilitating lung disease with limited treatment options and an unclear genetic basis.
• Bleomycin chemotherapy models pulmonary fibrosis, showing strain-dependent responses in mice (C57BL/6J vs. C3H/HeJ).
• Previous studies mapped susceptibility loci Blmpf1 and Blmpf2 for bleomycin-induced pulmonary fibrosis.

Purpose of the Study:

• To identify the quantitative trait gene responsible for the Blmpf2 locus.
• To investigate the role of genetic variation in Trim16 in the differential response to bleomycin-induced pulmonary fibrosis.

Main Methods:

• Histological phenotyping of bleomycin-induced lung disease in congenic mouse sublines to narrow down the genetic linkage region.
• Identification of Trim16 as a candidate gene with strain-dependent expression.
• Analysis of Trim16 promoter sequence variation.
• Over-expression of Trim16 via plasmid injection in mice.

Main Results:

• The linkage region for Blmpf2 was reduced to 13 genes, with Trim16 identified due to strain-dependent lung expression.
• Sequence variation in the Trim16 promoter explains its differential expression between mouse strains.
• Over-expression of Trim16 exacerbated pulmonary fibrosis and increased interleukin-12/23-p40 and neutrophil levels in bleomycin-treated mice.
• These findings mirrored the strain-specific differences observed between C57BL/6J and C3H/HeJ mice.

Conclusions:

• Genetic variation in Trim16 is responsible for its strain-dependent expression in the lung.
• Altered Trim16 expression affects susceptibility to bleomycin-induced pulmonary fibrosis in mice.
• Trim16 represents a potential therapeutic target for pulmonary fibrosis.