title: Paternal diet defines offspring chromatin state and intergenerational obesity.
abstract: The global rise in obesity has revitalized a search for genetic and epigenetic factors underlying the disease. We present a Drosophila model of paternal-diet-induced intergenerational metabolic reprogramming (IGMR) and identify genes required for its encoding in offspring. Intriguingly, we find that as little as 2 days of dietary intervention in fathers elicits obesity in offspring. Paternal sugar acts as a physiological suppressor of variegation, desilencing chromatin-state-defined domains in both mature sperm and in offspring embryos. We identify requirements for H3K9/K27me3-dependent reprogramming of metabolic genes in two distinct germline and zygotic windows. Critically, we find evidence that a similar system may regulate obesity susceptibility and phenotype variation in mice and humans. The findings provide insight into the mechanisms underlying intergenerational metabolic reprogramming and carry profound implications for our understanding of phenotypic variation and evolution.
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany; Department of Clinical and Experimental Medicine, Linkoping University, 58183 Linkoping, Sweden. Electronic address: anita.ost@liu.se.
authors.forename: Anita
authors.initials: A
authors.lastname: Öst
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany.
authors.forename: Adelheid
authors.initials: A
authors.lastname: Lempradl
authors.affiliation: Institut de Medicina Predictiva i Personalitzada del Càncer, Can Ruti Campus, Ctra. de Can Ruti, Camí de les Escoles s/n, 08916 Badalona, Barcelona, Spain; Josep Carreras Leukaemia Research Institute (IJC), ICO-Hospital GermansTrias i Pujol, 08916 Badalona, Barcelona, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Casas
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Weigert
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany.
authors.forename: Theodor
authors.initials: T
authors.lastname: Tiko
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany.
authors.forename: Merdin
authors.initials: M
authors.lastname: Deniz
authors.affiliation: Institut de Medicina Predictiva i Personalitzada del Càncer, Can Ruti Campus, Ctra. de Can Ruti, Camí de les Escoles s/n, 08916 Badalona, Barcelona, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Pantano
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Boenisch
authors.affiliation: Champalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal.
authors.forename: Pavel M
authors.initials: PM
authors.lastname: Itskov
authors.affiliation: Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Marlon
authors.initials: M
authors.lastname: Stoeckius
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Ruf
authors.affiliation: Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Rajewsky
authors.affiliation: Institute of Biology, Developmental Genetics, Martin Luther University Halle, 06120 Halle, Germany.
authors.forename: Gunter
authors.initials: G
authors.lastname: Reuter
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Iovino
authors.affiliation: Champalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Ribeiro
authors.affiliation: Department of Clinical and Experimental Medicine, Linkoping University, 58183 Linkoping, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Alenius
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Heyne
authors.affiliation: Institut de Medicina Predictiva i Personalitzada del Càncer, Can Ruti Campus, Ctra. de Can Ruti, Camí de les Escoles s/n, 08916 Badalona, Barcelona, Spain; Josep Carreras Leukaemia Research Institute (IJC), ICO-Hospital GermansTrias i Pujol, 08916 Badalona, Barcelona, Spain.
authors.forename: Tanya
authors.initials: T
authors.lastname: Vavouri
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany. Electronic address: pospisilik@ie-freiburg.mpg.de.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Pospisilik
mesh_terms: D000818:Animals; D050260:Carbohydrate Metabolism; D004032:Diet; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000378:metabolism; D044127:Epigenesis, Genetic; D005127:Eye Color; D005260:Female; D020022:Genetic Predisposition to Disease; D006570:Heterochromatin / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D013094:Spermatozoa / Q000378:metabolism
chemical_list: D006570:Heterochromatin