Lin28A Binds Active Promoters and Recruits Tet1 to Regulate Gene Expression

Mol Cell. 2016 Jan 7;61(1):153-60. doi: 10.1016/j.molcel.2015.11.020. Epub 2015 Dec 17.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line
  • DNA Methylation
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Embryonic Stem Cells / metabolism*
  • Epigenesis, Genetic
  • Gene Expression Regulation*
  • Mice
  • Promoter Regions, Genetic*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA Interference
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Transcriptional Activation*
  • Transfection


  • DNA-Binding Proteins
  • Lin-28 protein, mouse
  • Proto-Oncogene Proteins
  • RNA-Binding Proteins
  • TET1 protein, mouse