title: In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism.
abstract: Adverse prenatal environments can promote metabolic disease in offspring and subsequent generations. Animal models and epidemiological data implicate epigenetic inheritance, but the mechanisms remain unknown. In an intergenerational developmental programming model affecting F2 mouse metabolism, we demonstrate that the in utero nutritional environment of F1 embryos alters the germline DNA methylome of F1 adult males in a locus-specific manner. Differentially methylated regions are hypomethylated and enriched in nucleosome-retaining regions. A substantial fraction is resistant to early embryo methylation reprogramming, which may have an impact on F2 development. Differential methylation is not maintained in F2 tissues, yet locus-specific expression is perturbed. Thus, in utero nutritional exposures during critical windows of germ cell development can impact the male germline methylome, associated with metabolic disease in offspring.
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG UK.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Radford
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG UK.
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Ito
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG UK.
authors.forename: Hui
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG UK.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Corish
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG UK.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Yamazawa
authors.affiliation: Research Division, Joslin Diabetes Center and Harvard Medical School, 1 Joslin Place, Boston, MA 02215, USA.
authors.forename: Elvira
authors.initials: E
authors.lastname: Isganaitis
authors.affiliation: The Babraham Institute, Babraham, Cambridge.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Seisenberger
authors.affiliation: The Babraham Institute, Babraham, Cambridge.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hore
authors.affiliation: The Babraham Institute, Babraham, Cambridge.
authors.forename: Wolf
authors.initials: W
authors.lastname: Reik
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.|Faculty of Sciences, University of Basel, Basel, Switzerland.|Swiss Institute of Bioinformatics, Basel, Switzerland.
authors.forename: Serap
authors.initials: S
authors.lastname: Erkek
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.|Faculty of Sciences, University of Basel, Basel, Switzerland.
authors.forename: Antoine H F M
authors.initials: AHFM
authors.lastname: Peters
authors.affiliation: Research Division, Joslin Diabetes Center and Harvard Medical School, 1 Joslin Place, Boston, MA 02215, USA.
authors.forename: Mary-Elizabeth
authors.initials: ME
authors.lastname: Patti
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG UK.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Ferguson-Smith
mesh_terms: D000818:Animals; D031204:Caloric Restriction; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D048070:Fetal Nutrition Disorders / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D008659:Metabolic Diseases / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009707:Nucleosomes / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D013094:Spermatozoa / Q000378:metabolism* / Q000502:physiology
chemical_list: D007328:Insulin; D009707:Nucleosomes