LINE-1 Evasion of Epigenetic Repression in Humans

Francisco J. Sanchez-Luque, Marie-Jeanne H. C. Kempen, Patricia Gerdes, Dulce B. Vargas-Landin, Sandra R. Richardson, Robin-Lee Troskie, J. Samuel Jesuadian, Seth W. Cheetham, Patricia E. Carreira, Carmen Salvador-Palomeque, Marta García-Cañadas, Martin Muñoz-Lopez, Laura Sanchez, Mischa Lundberg, Angela Macia, Sara R. Heras, Paul M. Brennan, Ryan Lister, Jose L. Garcia-Perez, Adam D. EwingGeoffrey J. Faulkner

Research output: Contribution to journalArticlepeer-review

Abstract

Epigenetic silencing defends against LINE-1 (L1) retrotransposition in mammalian cells. However, the mechanisms that repress young L1 families and how L1 escapes to cause somatic genome mosaicism in the brain remain unclear. Here we report that a conserved Yin Yang 1 (YY1) transcription factor binding site mediates L1 promoter DNA methylation in pluripotent and differentiated cells. By analyzing 24 hippocampal neurons with three distinct single-cell genomic approaches, we characterized and validated a somatic L1 insertion bearing a 3ʹ transduction. The source (donor) L1 for this insertion was slightly 5ʹ truncated, lacked the YY1 binding site, and was highly mobile when tested in vitro. Locus-specific bisulfite sequencing revealed that the donor L1 and other young L1s with mutated YY1 binding sites were hypomethylated in embryonic stem cells, during neurodifferentiation, and in liver and brain tissue. These results explain how L1 can evade repression and retrotranspose in the human body.
Original languageEnglish
Pages (from-to)590-604.e12
Number of pages27
JournalMolecular Cell
Volume75
Issue number3
Early online date20 Jun 2019
DOIs
Publication statusPublished - Aug 2019

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