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Paternal Diet Defines Offspring Chromatin State and Intergenerational Obesity

Öst, Anita, Lempradl, Adelheid, Casas, Eduard, Weigert, Melanie, Tiko, Theodor, Deniz, Merdin, Pantano, Lorena, Boenisch, Ulrike, Itskov, Pavel M., Stoeckius, Marlon, Ruf, Marius, Rajewsky, Nikolaus, Reuter, Gunter, Iovino, Nicola, Ribeiro, Carlos, Alenius, Mattias, Heyne, Steffen, Vavouri, Tanya, Pospisilik, J. Andrew
Cell 2014 v.159 pp. 1352-1364
Drosophila, chromatin, diet, epigenetics, evolution, fathers, genes, humans, mice, models, nutritional intervention, obesity, phenotype, phenotypic variation, progeny, spermatozoa, sugars
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.