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 Ewing & 1 others Geoffrey J Faulkner

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 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.

Original languageEnglish
Article numbere12
Pages (from-to)590-604
JournalMolecular Cell
Volume75
Issue number3
Early online date20 Jun 2019
DOIs
Publication statusPublished - 8 Aug 2019

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Epigenetic Repression
Yin-Yang
Binding Sites
Mosaicism
Brain
DNA Methylation
Embryonic Stem Cells
Human Body
Epigenomics
Transcription Factors
Genome
Neurons
Liver

Cite this

Sanchez-Luque, F. J., Kempen, M-J. H. C., Gerdes, P., Vargas-Landin, D. B., Richardson, S. R., Troskie, R-L., ... Faulkner, G. J. (2019). LINE-1 evasion of epigenetic repression in humans. Molecular Cell, 75(3), 590-604. [e12]. https://doi.org/10.1016/j.molcel.2019.05.024
Sanchez-Luque, Francisco J ; Kempen, Marie-Jeanne H C ; Gerdes, Patricia ; Vargas-Landin, Dulce B ; Richardson, Sandra R ; Troskie, Robin-Lee ; Jesuadian, J Samuel ; Cheetham, Seth W ; Carreira, Patricia E ; Salvador-Palomeque, Carmen ; García-Cañadas, Marta ; Muñoz-Lopez, Martin ; Sanchez, Laura ; Lundberg, Mischa ; Macia, Angela ; Heras, Sara R ; Brennan, Paul M ; Lister, Ryan ; Garcia-Perez, Jose L ; Ewing, Adam D ; Faulkner, Geoffrey J. / LINE-1 evasion of epigenetic repression in humans. In: Molecular Cell. 2019 ; Vol. 75, No. 3. pp. 590-604.
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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 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.",
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Sanchez-Luque, FJ, Kempen, M-JHC, Gerdes, P, Vargas-Landin, DB, Richardson, SR, Troskie, R-L, 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 2019, 'LINE-1 evasion of epigenetic repression in humans' Molecular Cell, vol. 75, no. 3, e12, pp. 590-604. https://doi.org/10.1016/j.molcel.2019.05.024

LINE-1 evasion of epigenetic repression in humans. / Sanchez-Luque, Francisco J; Kempen, Marie-Jeanne H C; Gerdes, Patricia; Vargas-Landin, Dulce B; Richardson, Sandra R; Troskie, Robin-Lee; Jesuadian, J Samuel; Cheetham, Seth W; Carreira, Patricia E; Salvador-Palomeque, Carmen; García-Cañadas, Marta; Muñoz-Lopez, Martin; Sanchez, Laura; Lundberg, Mischa; Macia, Angela; Heras, Sara R; Brennan, Paul M; Lister, Ryan; Garcia-Perez, Jose L; Ewing, Adam D; Faulkner, Geoffrey J.

In: Molecular Cell, Vol. 75, No. 3, e12, 08.08.2019, p. 590-604.

Research output: Contribution to journalArticle

TY - JOUR

T1 - LINE-1 evasion of epigenetic repression in humans

AU - Sanchez-Luque, Francisco J

AU - Kempen, Marie-Jeanne H C

AU - Gerdes, Patricia

AU - Vargas-Landin, Dulce B

AU - Richardson, Sandra R

AU - Troskie, Robin-Lee

AU - Jesuadian, J Samuel

AU - Cheetham, Seth W

AU - Carreira, Patricia E

AU - Salvador-Palomeque, Carmen

AU - García-Cañadas, Marta

AU - Muñoz-Lopez, Martin

AU - Sanchez, Laura

AU - Lundberg, Mischa

AU - Macia, Angela

AU - Heras, Sara R

AU - Brennan, Paul M

AU - Lister, Ryan

AU - Garcia-Perez, Jose L

AU - Ewing, Adam D

AU - Faulkner, Geoffrey J

PY - 2019/8/8

Y1 - 2019/8/8

N2 - 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 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.

AB - 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 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.

U2 - 10.1016/j.molcel.2019.05.024

DO - 10.1016/j.molcel.2019.05.024

M3 - Article

VL - 75

SP - 590

EP - 604

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 3

M1 - e12

ER -

Sanchez-Luque FJ, Kempen M-JHC, Gerdes P, Vargas-Landin DB, Richardson SR, Troskie R-L et al. LINE-1 evasion of epigenetic repression in humans. Molecular Cell. 2019 Aug 8;75(3):590-604. e12. https://doi.org/10.1016/j.molcel.2019.05.024