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

Science. 2015 Nov 6;350(6261):aab2006. doi: 10.1126/science.aab2006. Epub 2015 Oct 8.

Authors

Affiliations

¹ Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
² Friedrich Miescher Institute for Biomedical Research (FMI), CH-4058 Basel, Switzerland. Faculty of Sciences, University of Basel, Basel, Switzerland.
³ Department of Animal Science, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Quebec, Canada.
⁴ Department of Pediatrics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
⁵ Department of Animal Science, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Quebec, Canada. Institute of Parasitology, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Quebec, Canada.
⁶ MRC Integrative Epidemiology Unity, School of Social and Community Medicine, University of Bristol, Bristol, UK.
⁷ McGill Centre for Bioinformatics, School of Computer Science, Faculty of Science, McGill University, Montreal, Quebec, Canada.
⁸ Department of Pediatrics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. Department of Human Genetics and Department of Pharmacology and Therapeutics, Research Institute of the McGill University Health Centre at the Montreal Children's Hospital, Montreal, Quebec, Canada.
⁹ Friedrich Miescher Institute for Biomedical Research (FMI), CH-4058 Basel, Switzerland. Faculty of Sciences, University of Basel, Basel, Switzerland. sarah.kimmins@mcgill.ca antoine.peters@fmi.ch.
¹⁰ Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. Department of Animal Science, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Quebec, Canada. sarah.kimmins@mcgill.ca antoine.peters@fmi.ch.

PMID: 26449473
DOI: 10.1126/science.aab2006

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Histones
RNA, Messenger
Histone Demethylases
KDM1a protein, mouse

Grants and funding

Canadian Institutes of Health Research/Canada