Zfp217 mediates m6A mRNA methylation to orchestrate transcriptional and post-transcriptional regulation to promote adipogenic differentiation.

ABSTRACT

A complex and highly orchestrated gene expression program chiefly establishes the properties that define the adipocyte phenotype, in which the vast majority of factors are involved in transcriptional regulation. However, the mechanisms by post-transcriptional modulation are poorly understood. Here, we showed that zinc finger protein (Zfp217) couples gene transcription to m6A mRNA modification to facilitate adipogenesis. Zfp217 modulates m6A mRNA methylation by activating the transcription of m6A demethylase FTO. Consistently, depletion of Zfp217 compromises adipogenic differentiation of 3T3L1 cells and results in a global increase of m6A modification. Moreover, the interaction of Zfp217 with YTHDF2 is critical for allowing FTO to maintain its interaction with m6A sites on various mRNAs, as loss of Zfp217 leads to FTO decrease and augmented m6A levels. These findings highlight a role for Zfp217-dependent m6A modification to coordinate transcriptional and post-transcriptional regulation and thus promote adipogenic differentiation.