Lin28A Binds Active Promoters and Recruits Tet1 to Regulate Gene Expression

Yaxue Zeng; Bing Yao; Jaehoon Shin; Li Lin; Namshik Kim; Qifeng Song; Shuang Liu; Yijing Su; Junjie U Guo; Luoxiu Huang; Jun Wan; Hao Wu; Jiang Qian; Xiaodong Cheng; Heng Zhu; Guo-li Ming; Peng Jin; Hongjun Song

doi:10.1016/j.molcel.2015.11.020

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.

Authors

Yaxue Zeng¹, Bing Yao², Jaehoon Shin³, Li Lin², Namshik Kim¹, Qifeng Song⁴, Shuang Liu⁴, Yijing Su¹, Junjie U Guo⁵, Luoxiu Huang², Jun Wan⁶, Hao Wu⁷, Jiang Qian⁶, Xiaodong Cheng⁸, Heng Zhu⁴, Guo-li Ming⁹, Peng Jin¹⁰, Hongjun Song¹¹

Affiliations

¹ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
³ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶ Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁷ Department of Biostatistics and Bioinformatics, Emory University School of Medicine, Atlanta, GA 30322, USA.
⁸ Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
⁹ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹⁰ Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: peng.jin@emory.edu.
¹¹ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: shongju1@jhmi.edu.

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.

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding