Disruption of histone methylation in developing sperm impairs offspring health transgenerationally

被引：364

作者：

Siklenka, Keith ^{[1
]}

Erkek, Serap ^{[2
,3
]}

Godmann, Maren ^{[4
]}

Lambrot, Romain ^{[4
]}

McGraw, Serge ^{[5
]}

Lafleur, Christine ^{[4
]}

Cohen, Tamara ^{[4
]}

Xia, Jianguo ^{[4
,6
]}

Suderman, Matthew ^{[7
]}

Hallett, Michael ^{[8
]}

Trasler, Jacquetta ^{[5
,9
,10
]}

Peters, Antoine H. F. M. ^{[2
,3
]}

Kimmins, Sarah ^{[1
,4
]}

机构：

[1] McGill Univ, Fac Med, Dept Pharmacol & Therapeut, Montreal, PQ, Canada

[2] Friedrich Miescher Inst Biomed Res FMI, CH-4058 Basel, Switzerland

[3] Univ Basel, Fac Sci, Basel, Switzerland

[4] McGill Univ, Fac Agr & Environm Sci, Dept Anim Sci, Montreal, PQ, Canada

[5] McGill Univ, Fac Med, Dept Pediat, Montreal, PQ, Canada

[6] McGill Univ, Fac Agr & Environm Sci, Inst Parasitol, Montreal, PQ, Canada

[7] Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unity, Bristol, Avon, England

[8] McGill Univ, Fac Sci, Sch Comp Sci, McGill Ctr Bioinformat, Montreal, PQ, Canada

[9] McGill Univ, Montreal Childrens Hosp, Ctr Hlth, Res Inst,Dept Human Genet, Montreal, PQ H3H 1P3, Canada

[10] McGill Univ, Montreal Childrens Hosp, Ctr Hlth, Dept Pharmacol & Therapeut,Res Inst, Montreal, PQ H3H 1P3, Canada

来源：

SCIENCE | 2015年 / 350卷 / 6261期

基金：

瑞士国家科学基金会;

关键词：

DNA METHYLATION; MUTATION-RATES; MOUSE; INHERITANCE; CHROMATIN; LSD1; RNA; EXPRESSION; MARKS; PDK1;

D O I：

10.1126/science.aab2006

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

A father's lifetime experiences can be transmitted to his offspring to affect health and development. However, the mechanisms underlying paternal epigenetic transmission are unclear. Unlike in somatic cells, there are few nucleosomes in sperm, and their function in epigenetic inheritance is unknown. We generated transgenic mice in which overexpression of the histone H3 lysine 4 (H3K4) demethylase KDM1A (also known as LSD1) during spermatogenesis reduced H3K4 dimethylation in sperm. KDM1A overexpression in one generation severely impaired development and survivability of offspring. These defects persisted transgenerationally in the absence of KDM1A germline expression and were associated with altered RNA profiles in sperm and offspring. We show that epigenetic inheritance of aberrant development can be initiated by histone demethylase activity in developing sperm, without changes to DNA methylation at CpG-rich regions.

引用

页数：13

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