Sanchez-Luque, Francisco JKempen, Marie-Jeanne H CGerdes, PatriciaVargas-Landin, Dulce BRichardson, Sandra RTroskie, Robin-LeeJesuadian, J SamuelCheetham, Seth WCarreira, Patricia ESalvador-Palomeque, CarmenGarcía-Cañadas, MartaMuñoz-Lopez, MartinSanchez, LauraLundberg, MischaMacia, AngelaHeras, Sara RBrennan, Paul MLister, RyanGarcia-Perez, Jose LEwing, Adam DFaulkner, Geoffrey J2023-01-252023-01-252019-06-20http://hdl.handle.net/10668/14159Epigenetic 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 3' transduction. The source (donor) L1 for this insertion was slightly 5' 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.enDNA methylationL1LINE-1YY1epigeneticsneuroscienceretrotransposonsingle-cell genomicsBinding SitesDNA MethylationDNA-Binding ProteinsEpigenetic RepressionGenome, HumanHippocampusHumansLiverLong Interspersed Nucleotide ElementsNeuronsRetroelementsSingle-Cell AnalysisYY1 Transcription Factorresearch article31230816open access10.1016/j.molcel.2019.05.0241097-4164http://www.cell.com/article/S109727651930396X/pdf