LINE-1 Evasion of Epigenetic Repression in Humans

Sánchez Luque, Francisco José; García Cañadas, Marta; Muñoz López, Martin; Rodríguez Heras, Sara; García Pérez, José Luis

doi:10.1016/j.molcel.2019.05.024

2019 Sanchez-Luque et al Mol Cell.pdf (5.541Mo)

Identificadores

URI: https://hdl.handle.net/10481/88588

DOI: 10.1016/j.molcel.2019.05.024

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Editorial

Elsevier

Date

2019

Referencia bibliográfica

Sanchez-Luque FJ, Kempen MHC, Gerdes P, Vargas-Landin DB, Richardson SR, Troskie RL, Jesuadian JS, Cheetham SW, Carreira PE, Salvador-Palomeque C, García-Cañadas M, Muñoz-Lopez M, Sanchez L, Lundberg M, Macia A, Heras SR, Brennan PM, Lister R, Garcia-Perez JL, Ewing AD, Faulkner GJ. LINE-1 Evasion of Epigenetic Repression in Humans. Mol Cell. 2019 Aug 8;75(3):590-604.e12. doi: 10.1016/j.molcel.2019.05.024. Epub 2019 Jun 20. PMID: 31230816.

Patrocinador

This study was supported by the People Programme (Marie Curie Actions) of the European Union Seventh Framework Program (FP7/2007-2013) under REA grant agreement PIOF-GA-2013-623324 (to F.J.S.-L.), an NHMRC Early Career Fellowship (GNT1161832 to S.W.C.),ARC Discovery Early Career Researcher Award (DE150101117) and Discovery Project (DP170101198) grants (to A.D.E.). J.L.G.-P. acknowledges funding from CICE-FEDER-P12-CTS-2256, Plan Nacional de I+D+I 2013–2016 (FISFEDER- PI14/02152), PCIN-2014-115-ERA-NET NEURON II, the European Research Council (ERC-Consolidator ERC-STG-2012-309433), an International Early Career Scientist grant from the Howard Hughes Medical Institute (IECS-55007420), and The Wellcome Trust-University of Edinburgh Institutional Strategic Support Fund (ISFF2). G.J.F. acknowledges support from the Mater Foundation, a CSL Centenary Fellowship, and NHMRC Project grants GNT1106206, GNT1125645, GNT1126393, and GNT1138795

Résumé

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 singlecell 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. Locusspecific 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.

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