Tet2 interacts with SCAN domain and regulates Zscan4-associated events during cell reprogramming (RNA-Seq)

Evolutionarily conserved SCAN domain-containing zinc finger transcription factors (ZSCAN) have been found in both the mouse and human genomes. Of which, Zscan4 is crucial for zygotic genome activation (ZGA) in preimplantation embryos, and induced pluripotent stem cell (iPSC) reprogramming. However, little is known about the mechanism of Zscan4 underlying these processes of cell fate control. Here we show that Zscan4f, a representative of ZSCAN proteins, is able to recruit Tet2 through its SCAN domain. The Zscan4f-Tet2 interaction promotes DNA demethylation and regulates the expression of target genes, particularly those encoding glycolytic enzymes and proteasome subunits. Disruption of the Zscan4f-Tet2 interaction impairs cellular metabolism, proteasome function, and ultimately compromises iPSC generation. These results identify Tet2 as a major cooperator for the function of Zscan4f, and suggest a common mechanism shared by SCAN family transcription factors to recruit TET DNA dioxygenases to regulate diverse cellular processes. Overall design: Transcriptome analysis was performed in D4-OSKM-2ndMEFs (3 groups, n=3 per group).