L1 retrotransposition is activated by Ten-eleven-translocation protein 1 and repressed by methyl-CpG binding proteins

Nucleus
Peng ZhangM Cristina Cardoso

Abstract

One of the major functions of DNA methylation is the repression of transposable elements, such as the long-interspersed nuclear element 1 (L1). The underlying mechanism(s), however, are unclear. Here, we addressed how retrotransposon activation and mobilization are regulated by methyl-cytosine modifying ten-eleven-translocation (Tet) proteins and how this is modulated by methyl-CpG binding domain (MBD) proteins. We show that Tet1 activates both, endogenous and engineered L1 retrotransposons. Furthermore, we found that Mecp2 and Mbd2 repress Tet1-mediated activation of L1 by preventing 5hmC formation at the L1 promoter. Finally, we demonstrate that the methyl-CpG binding domain, as well as the adjacent non-sequence specific DNA binding domain of Mecp2 are each sufficient to mediate repression of Tet1-induced L1 mobilization. Our study reveals a mechanism how L1 elements get activated in the absence of Mecp2 and suggests that Tet1 may contribute to Mecp2/Mbd2-deficiency phenotypes, such as the Rett syndrome. We propose that the balance between methylation "reader" and "eraser/writer" controls L1 retrotransposition.

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Citations

Feb 6, 2018·Chromosome Research : an International Journal on the Molecular, Supramolecular and Evolutionary Aspects of Chromosome Biology·Elisa OrecchiniAlessandro Michienzi
Mar 15, 2019·Nature Reviews. Genetics·Özgen DenizMiguel R Branco
Apr 9, 2020·Cells·Annika SchmidtM Cristina Cardoso
Jul 14, 2018·Mobile DNA·Geoffrey J Faulkner, Victor Billon
Dec 24, 2019·Journal of Molecular Biology·Cathia RauschM Cristina Cardoso
May 11, 2021·Frontiers in Genetics·Osman Sharifi, Dag H Yasui
Jun 17, 2021·Nucleic Acids Research·Cathia RauschM Cristina Cardoso

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Methods Mentioned

BETA
transfection
flow cytometry
PCR
histone
RNA-seq
transgenic
FCS
Assay

Software Mentioned

Operetta
GluMs
UCSC genome browser
Harmony
DESeq2
Nextera
STAR
TEtranscript

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