摘要：The expression of
Igf2 in mammals shows a complex regulation involving multiple promoters and epigenetic mechanisms. We previously identified a novel regulatory mechanism based on the interaction between the transcriptional factor ZBED6 and
Igf2 intron. Disruption of the ZBED6-
Igf2 interaction leads to a dramatic up-regulation of IGF2 expression postnatally. In the current study we characterize an additional layer of regulation involving
miR483 encoded by another
Igf2 intron. We found a highly significant up-regulation of
miR483 expression when the ZBED6-
Igf2 axis is disrupted in transgenic mice. Furthermore, CRISPR/Cas9 mediated knock-out of
miR483 in C2C12 myoblast cells, both wild-type and cells with disrupted ZBED6-
Igf2 axis (
Igf2
dGGCT), resulted in down-regulation of
Igf2 expression and a reduced proliferation rate. This was further validated using
miR483 mimics and inhibitors. RNA-seq analysis revealed a significant enrichment of genes involved in the PI3K-Akt signaling pathway among genes down-regulated in
miR483
−/− cells, including
Igf2 down-regulation. The opposite pattern was observed in
Igf2
dGGCT cells, where
Igf2 is up-regulated. Our data suggest a positive feedback between
miR483 and
Igf2 promoter activity, strongly affecting how ZBED6 controls
Igf2 expression in various cell types.
