LINE-1 Evasion of Epigenetic Repression in Humans

被引：91

作者：

Sanchez-Luque, Francisco J. ^{[1
,2
]}

Kempen, Marie-Jeanne H. C. ^{[1
,3
]}

Gerdes, Patricia ^{[1
]}

Vargas-Landin, Dulce B. ^{[4
,5
]}

Richardson, Sandra R. ^{[1
]}

Troskie, Robin-Lee ^{[1
]}

Jesuadian, J. Samuel ^{[1
]}

Cheetham, Seth W. ^{[1
]}

Carreira, Patricia E. ^{[1
]}

Salvador-Palomeque, Carmen ^{[1
]}

Garcia-Canadas, Marta ^{[2
]}

Munoz-Lopez, Martin ^{[2
]}

Sanchez, Laura ^{[2
]}

Lundberg, Mischa ^{[1
]}

Macia, Angela ^{[6
]}

Heras, Sara R. ^{[2
,7
]}

Brennan, Paul M. ^{[8
]}

Lister, Ryan ^{[4
,5
]}

Garcia-Perez, Jose L. ^{[2
,3
]}

Ewing, Adam D. ^{[1
]}

Faulkner, Geoffrey J. ^{[1
,9
]}

机构：

[1] Univ Queensland, Mater Res Inst, TRI Bldg, Woolloongabba, Qld 4102, Australia

[2] Pfizer Univ Granada, Andalusian Reg Govt, GENYO Ctr Genom & Oncol Res, Avda Ilustrac 114, Pts Granada 18016, Spain

[3] Univ Edinburgh, Western Gen Hosp, IGMM, MRC,Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland

[4] Univ Western Australia, Sch Mol Sci, Ctr Excellence Plant Energy Biol, Australian Res Council, Perth, WA 6009, Australia

[5] Harry Perkins Inst Med Res, Perth, WA 6009, Australia

[6] Univ Calif San Diego, Rady Childrens Hosp San Diego, Sch Med, Dept Pediat, La Jolla, CA 92093 USA

[7] Univ Granada, Fac Pharm, Dept Biochem & Mol Biol 2, Campus Univ Cartuja, E-18071 Granada, Spain

[8] Western Gen Hosp, Edinburgh Canc Res Ctr, Edinburgh EH4 2XR, Midlothian, Scotland

[9] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia

来源：

MOLECULAR CELL | 2019年 / 75卷 / 03期

基金：

英国惠康基金; 欧洲研究理事会; 澳大利亚研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

L1; RETROTRANSPOSITION; SOMATIC RETROTRANSPOSITION; TRANSPOSABLE ELEMENTS; GENE-EXPRESSION; STEM-CELLS; DNA; TRANSCRIPTION; MOSAICISM; GENOME; MOUSE;

D O I：

10.1016/j.molcel.2019.05.024

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：590 / +

页数：27

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