ZBED6 regulates Igf2 expression partially through its regulation of miR483 expression

Abstract

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 (Igf2dGGCT), 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 Igf2dGGCT 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.

Ablation of ZC3H11A causes early embryonic lethality and dysregulation of metabolic processes

“…Zc3h11a is located on chromosome 1 in both human and mouse genomes and harbors the coding sequence of another gene encoding the DNA-binding zinc-finger protein ZBED6 ( 13 – 18 ) ( Fig. 1 A ).…”

Sexual dimorphism of circadian liver transcriptome

“…Functional signatures of the genes with male-specific oscillation under CR were involved in transcription and RNA processing, as well as immune response and DNA repair ( Figure 4 E). TFs that were predicted for this group of genes included coactivator of androgen receptor (AR) MYSM1 40 which seems to have predicted target genes among male-rhythmic gene population irrespective of the diet, histone N-methyltransferase ASH1L, 50 Igf2—repressor ZBED6 51 and NFAT5 involved in regulation of immune responses 52 ( Figure 4 F). The genes that were rhythmic specifically in female liver showed association with fatty acid metabolism, protein transport, glycolysis, autophagy, and unfolded protein response ( Figure 4 E).…”

Efficient Editing of the ZBED6-Binding Site in Intron 3 of IGF2 in a Bovine Model Using the CRISPR/Cas9 System

“…ZBED6 is an important transcription factor that regulates IGF2 expression by binding a conserved motif (GCTCG) [ 11 , 23 ]. Knockout of the ZBED6-binding site can enhance IGF2 expression at the cellular level and increase the proliferative ability of muscle cells.…”