Lin28A Binds Active Promoters and Recruits Tet1 to Regulate Gene Expression

Lin28, a well-known RNA-binding protein, regulates diverse cellular properties. All physiological functions of Lin28A characterized so far have been attributed to its repression of let-7 miRNA biogenesis or modulation of mRNA translational efficiency. Here we show that Lin28A directly binds to a consensus DNA sequence in vitro and in mouse embryonic stem cells in vivo. ChIP-seq and RNA-seq reveal enrichment of Lin28A binding around transcription start sites and a positive correlation between its genomic occupancy and expression of many associated genes. Mechanistically, Lin28A recruits 5-methylcytosine-dioxygenase Tet1 to genomic binding sites to orchestrate 5-methylcytosine and 5-hydroxymethylcytosine dynamics. Either Lin28A or Tet1 knockdown leads to dysregulated DNA methylation and expression of common target genes. These results reveal a surprising role for Lin28A in transcriptional regulation via epigenetic DNA modifications and have implications for understanding mechanisms underlying versatile functions of Lin28A in mammalian systems. RNA-binding protein Lin28A shapes the post-transcriptional gene expression by influencing RNA metabolism. Zeng et al. define a DNA binding characteristic of Lin28A, providing evidence for its ability to directly regulate transcription. Lin28A preferentially recognizes transcription initiation loci and recruits DNA demethylase Tet1 to modulate target cytosine modification dynamics and, ultimately, transcription.