Disruption of histone methylation in developing sperm impairs offspring health transgenerationally

Keith Siklenka; Serap Erkek; Maren Godmann; Romain Lambrot; Serge McGraw; Christine Lafleur; Tamara Cohen; Jianguo Xia; Matthew Suderman; Michael Hallett; Jacquetta Trasler; Antoine H F M Peters; Sarah Kimmins

doi:10.1126/science.aab2006

Disruption of histone methylation in developing sperm impairs offspring health transgenerationally

Keith Siklenka, Serap Erkek, Maren Godmann, Romain Lambrot, Serge McGraw, Christine Lafleur, Tamara Cohen, Jianguo Xia, Matthew Suderman, Michael Hallett, Jacquetta Trasler, Antoine H F M Peters, Sarah Kimmins

Research output: Contribution to journal › Article (Academic Journal) › peer-review

401 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	aab2006
Journal	Science
Volume	350
Issue number	6261
DOIs	https://doi.org/10.1126/science.aab2006
Publication status	Published - 6 Nov 2015

Keywords

Animals
Congenital Abnormalities/genetics
CpG Islands
DNA Methylation
Epigenesis, Genetic
Female
Gene Expression Regulation, Developmental
Histone Demethylases/genetics
Histones/metabolism
Male
Methylation
Mice
Mice, Transgenic
RNA, Messenger/metabolism
Spermatogenesis/genetics
Spermatozoa/enzymology

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Dr Matthew J Suderman
- matthew.sudermanbristol.acuk
- Bristol Medical School (PHS) - Associate Professor in Molecular Epidemiology
- Bristol Population Health Science Institute
- MRC Integrative Epidemiology Unit
Person: Academic , Member

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title = "Disruption of histone methylation in developing sperm impairs offspring health transgenerationally",

abstract = "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. ",

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author = "Keith Siklenka and Serap Erkek and Maren Godmann and Romain Lambrot and Serge McGraw and Christine Lafleur and Tamara Cohen and Jianguo Xia and Matthew Suderman and Michael Hallett and Jacquetta Trasler and Peters, {Antoine H F M} and Sarah Kimmins",

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T1 - Disruption of histone methylation in developing sperm impairs offspring health transgenerationally

AU - Siklenka, Keith

AU - Erkek, Serap

AU - Godmann, Maren

AU - Lambrot, Romain

AU - McGraw, Serge

AU - Lafleur, Christine

AU - Cohen, Tamara

AU - Xia, Jianguo

AU - Suderman, Matthew

AU - Hallett, Michael

AU - Trasler, Jacquetta

AU - Peters, Antoine H F M

AU - Kimmins, Sarah

PY - 2015/11/6

Y1 - 2015/11/6

N2 - 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.

AB - 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.

KW - Animals

KW - Congenital Abnormalities/genetics

KW - CpG Islands

KW - DNA Methylation

KW - Epigenesis, Genetic

KW - Female

KW - Gene Expression Regulation, Developmental

KW - Histone Demethylases/genetics

KW - Histones/metabolism

KW - Male

KW - Methylation

KW - Mice

KW - Mice, Transgenic

KW - RNA, Messenger/metabolism

KW - Spermatogenesis/genetics

KW - Spermatozoa/enzymology

U2 - 10.1126/science.aab2006

DO - 10.1126/science.aab2006

M3 - Article (Academic Journal)

C2 - 26449473

SN - 0036-8075

VL - 350

SP - aab2006

JO - Science

JF - Science

IS - 6261

ER -

Disruption of histone methylation in developing sperm impairs offspring health transgenerationally

Abstract

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Dr Matthew J Suderman

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