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.
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Keith
authors.initials: K
authors.lastname: Siklenka
authors.affiliation: Friedrich Miescher Institute for Biomedical Research (FMI), CH-4058 Basel, Switzerland. Faculty of Sciences, University of Basel, Basel, Switzerland.
authors.forename: Serap
authors.initials: S
authors.lastname: Erkek
authors.affiliation: Department of Animal Science, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Quebec, Canada.
authors.forename: Maren
authors.initials: M
authors.lastname: Godmann
authors.affiliation: Department of Animal Science, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Quebec, Canada.
authors.forename: Romain
authors.initials: R
authors.lastname: Lambrot
authors.affiliation: Department of Pediatrics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Serge
authors.initials: S
authors.lastname: McGraw
authors.affiliation: Department of Animal Science, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Quebec, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Lafleur
authors.affiliation: Department of Animal Science, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Quebec, Canada.
authors.forename: Tamara
authors.initials: T
authors.lastname: Cohen
authors.affiliation: 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.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Xia
authors.affiliation: MRC Integrative Epidemiology Unity, School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Suderman
authors.affiliation: McGill Centre for Bioinformatics, School of Computer Science, Faculty of Science, McGill University, Montreal, Quebec, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Hallett
authors.affiliation: 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.
authors.forename: Jacquetta
authors.initials: J
authors.lastname: Trasler
authors.affiliation: 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.
authors.forename: Antoine H F M
authors.initials: AH
authors.lastname: Peters
authors.affiliation: 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.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kimmins
mesh_terms: D000818:Animals; D000013:Congenital Abnormalities / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D008297:Male; D008745:Methylation; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D013091:Spermatogenesis / Q000235:genetics*; D013094:Spermatozoa / Q000201:enzymology / Q000254:growth & development*
chemical_list: D006657:Histones; D012333:RNA, Messenger; D056466:Histone Demethylases; C504076:KDM1a protein, mouse