Lin28A Binds Active Promoters and Recruits Tet1 to Regulate Gene Expression

• Type of Material: Article
• Authors: Yaxue Zeng, Johns Hopkins University; Bing Yao, Emory University; Jaehoon Shin, Johns Hopkins University; Li Lin, Emory University; Namshik Kim, Johns Hopkins University; Qifeng Song, Johns Hopkins University; Shuang Liu, Johns Hopkins University; Yijing Su, Johns Hopkins University; Junjie Guo, Johns Hopkins University; Luoxiu Huang, Emory University; Jun Wan, Johns Hopkins University; Hao Wu, Emory University; Jiang Qian, Johns Hopkins University; Xiaodong Cheng, Emory University; Heng Zhu, Johns Hopkins University; Guo-li Ming, Johns Hopkins University; Peng Jin, Emory University; Hongjun Song, Johns Hopkins University
• Language: English
• Date: 2016-01-07
• Publisher: Elsevier (Cell Press)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Elsevier Inc.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.molcel.2015.11.020
• Title of Journal or Parent Work: Molecular Cell
• ISSN: 1097-2765
• Volume: 61
• Issue: 1
• Start Page: 153
• End Page: 160
• Grant/Funding Information: This work was supported by grants from NIH (NS047344 and MH087874) and MSCRF to H.S.; from NIH (NS079625 and HD073162) to P.J; from MSCRF and NIH (NS048271 and MH105128) and MSCRF to G.-l.M.; by postdoctoral fellowships from MSCRF to Y.Z., N.S.K.; by a postdoctoral fellowship from the National Ataxia Foundation to B.Y.
• Keywords: RNAS; EMBRYONIC STEM-CELLS; DEMETHYLATION; 5-METHYLCYTOSINE; MODULATION; Cell Biology; DNA METHYLATION; Life Sciences & Biomedicine; TRANSCRIPTIONAL REGULATION; INTERACTOME; Biochemistry & Molecular Biology; Science & Technology; ADULT BRAIN; GENOME
• Research Categories: Chemistry, Biochemistry; Biology, Genetics

Abstract

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.