Dataset Information

Lin28A Binds Active Promoters and Recruits Tet1 to Regulate Gene Expression.

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.

SUBMITTER: Zeng Y

PROVIDER: S-EPMC4779955 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Publications

Lin28A Binds Active Promoters and Recruits Tet1 to Regulate Gene Expression.

Zeng Yaxue Y Yao Bing B Shin Jaehoon J Lin Li L Kim Namshik N Song Qifeng Q Liu Shuang S Su Yijing Y Guo Junjie U JU Huang Luoxiu L Wan Jun J Wu Hao H Qian Jiang J Cheng Xiaodong X Zhu Heng H Ming Guo-li GL Jin Peng P Song Hongjun H

Molecular cell 20151217 1

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 ...[more]

PMID: 26711009

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Project description:The dynamic regulation of DNA methylation in postmitotic neurons is necessary for memory formation and other adaptive behaviors. Ten-eleven translocation 1 (TET1) plays a part in these processes by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), thereby initiating active DNA demethylation. However, attempts to pinpoint its exact role in the nervous system have been hindered by contradictory findings, perhaps due in part, to a recent discovery that two isoforms of the Tet1 gene are differentially expressed from early development into adulthood. Here, we demonstrate that both the shorter transcript (Tet1S ) encoding an N-terminally truncated TET1 protein and a full-length Tet1 (Tet1FL ) transcript encoding canonical TET1 are co-expressed in the adult mouse brain. We show that Tet1S is the predominantly expressed isoform and is highly enriched in neurons, whereas Tet1FL is generally expressed at lower levels and more abundant in glia, suggesting their roles are at least partially cell type-specific. Using viral-mediated, isoform and neuron-specific molecular tools, we find that the individual repression of each transcript leads to the dysregulation of unique gene ensembles and contrasting changes in basal synaptic transmission. In addition, Tet1S repression enhances, while Tet1FL impairs, hippocampal-dependent memory in male mice. Together, our findings demonstrate that each Tet1 isoform serves a distinct role in the mammalian brain.SIGNIFICANCE STATEMENT In the brain, activity-dependent changes in gene expression are required for the formation of long-term memories. DNA methylation plays an essential role in orchestrating these learning-induced transcriptional programs by influencing chromatin accessibility and transcription factor binding. Once thought of as a stable epigenetic mark, DNA methylation is now known to be impermanent and dynamically regulated, driving neuroplasticity in the brain. We found that Tet1, a member of the ten-eleven translocation (TET) family of enzymes that mediates removal of DNA methyl marks, is expressed as two separate isoforms in the adult mouse brain and that each differentially regulates gene expression, synaptic transmission and memory formation. Together, our findings demonstrate that each Tet1 isoform serves a distinct role in the CNS.

Dataset Information

Lin28A Binds Active Promoters and Recruits Tet1 to Regulate Gene Expression.

Publications

Lin28A Binds Active Promoters and Recruits Tet1 to Regulate Gene Expression.

Similar Datasets

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