Regulation of Tak1 alternative splicing by splice-switching oligonucleotides

Biochemical and Biophysical Research Communications
Donghu ZhouYing Jiang

Abstract

Alternative splicing (AS) generates multiple isoforms from a single precursor mRNA, and these isoforms usually exhibit different tissue distributions and functions. Aberrant protein isoforms can lead to abnormalities in protein function and may even result in genetic disorders or cancer. In recent years, splice-switching oligonucleotides (SSOs) have emerged as a promising therapeutic strategy for several neurological diseases, but the efficacy of this strategy in other organs is less reported. In this study, we designed and synthesized SSOs targeting the splicing regulators of exon 12 of the Tak1 gene, inducing variant switching between Tak1-A and Tak1-B. We also designed SSOs capable of knockdown both Tak1 variants by inducing the aberrant splicing of exon 4. The Vivo-morpholino SSOs showed significant splice-switching of Tak1 in mouse liver, with a persistence of at least 10 days after initial SSOs delivery. Bioinformatics analysis indicated a lipid metabolism-related function for Tak1-B but not Tak1-A. The conversion of Tak1-B to Tak1-A consistently led to significant accumulation of lipids in cultured AML12 cells, as well as the dysregulation of several lipid metabolism-related genes in mouse liver. Different functional pro...Continue Reading

Citations

Jul 28, 2020·International Journal of Molecular Sciences·Nina FrieseAndrea Hoffmann

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