Genomics

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Small and large RNA sequencing of mouse livers receiving small hairpin RNAs


ABSTRACT: Adeno-associated viral (AAV) small hairpin (shRNA) expression vectors are a promising therapeutic but can induce severe liver toxicity when delivered at high albeit undefined doses. Using various AAV-shRNA vectors under the high-expressing U6 and low-expressing H1 promoters, we found that dose-limiting toxicity was strongly correlated with an shRNA concentration of >12% of total microRNA levels. Toxicity was associated with a specific reduction in the first synthesized 22nt isoform of miR-122-5p, resulting in the specific de-repression of miR-122 target mRNAs. A causative link between miR-122 reduction and toxicity was established when an AAV-sh-miR-122 vector producing >20% of the total liver miRNAs prevented liver toxicity. Consistent with these results, miR-122 knockout mice, which in part adapt to an absence of miR-122 reduction, also show no toxicity with high dose AAV-shRNA delivery.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE69186 | GEO | 2016/03/09

SECONDARY ACCESSION(S): PRJNA284768

REPOSITORIES: GEO

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