Mechanism of microRNA-mediated global DNA demethylation in human iPS cells

Abstract

Global DNA demethylation is the most essential epigenetic mechanism for reprogramming somatic cells to induced pluripotent stem cells (iPS cells or iPSCs). However, none of Yamanaka factors (Oct4, Sox2, Klf4 and c-Myc) or Thomson factors (Oct4, Sox2, Nanog and Lin28) can define such an important mechanism. Our studies for the first time reveal that a unique family of microRNA (miRNA), namely miR-302, is responsible for inducing not only global DNA demethylation but also chromatin modification in human iPSCs and embryonic stem cells (ESCs). miR-302 functions to concurrently silence multiple key epigenetic regulators, such as AOF1 (LSD2, KDM1B), AOF2 (LSD1, KDM1), MECP1/2, DNMT1, and HDAC2, to reset genomic DNA methylation patterns and hence reactivate the full spectrum of ESC-specific transcriptome expression. Moreover, silencing AOF2 further destabilizes DNMT1 activity and prevents replication-dependent DNA remethylation during iPSC division. Inhibition of both AOF1 and AOF2 also increases methylation of histone 3 on lysine 4 (H3K4me2/3), a chromatin mark for ESCs and reprogrammed iPSCs. These epigenetic events highly resemble zygotic reprogramming during early embryonic development. In this review, through deciphering the function of miR302, we explain how nuclear reprogramming is initiated in iPSCs, of which the knowledge is useful for improving the efficiency of current iPSC generation technologies.