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Paternal diet defines offspring chromatin state and intergenerational obesity.

ABSTRACT: The global rise in obesity has revitalized a search to understand genetic, and in particular, epigenetic factors underlying the disease. We present a Drosophila model of paternal-diet-induced Inter-Generational Metabolic Reprogramming (IGMR) and identify genes required for its encoding in offspring. Intriguingly, we find that as little as two days of dietary intervention in fathers elicits obesity in offspring. Paternal sugar acts as a physiological suppressor of variegation, de-silencing chromatin state-defined transcriptional units 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 regulates 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.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE62668 | GEO | 2014/12/04

SECONDARY ACCESSION(S): PRJNA264746

REPOSITORIES: GEO

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Paternal diet defines offspring chromatin state and intergenerational obesity.

Project description:The global rise in obesity has revitalized a search to understand genetic, and in particular, epigenetic factors underlying the disease. We present a Drosophila model of paternal-diet-induced Inter-Generational Metabolic Reprogramming (IGMR) and identify genes required for its encoding in offspring. Intriguingly, we find that as little as two days of dietary intervention in fathers elicits obesity in offspring. Paternal sugar acts as a physiological suppressor of variegation, de-silencing chromatin state-defined transcriptional units 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 regulates 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. RNA-seq on Drosophila embryos and sperm samples fed medium and high sugar.

2014-12-04 | E-GEOD-62668 | biostudies-arrayexpress

Intergenerational metabolic priming by sperm piRNAs

Project description:Preconception parental environment can reproducibly program offspring phenotype without altering the DNA sequence, yet the mechanisms underpinning this ‘epigenetic inheritance’ remains elusive. Here, we demonstrate the existence of an intact piRNA-pathway in mature Drosophila sperm and show that pathway modulation alters offspring gene transcription in a sequence-specific manner. We map a dynamic small RNA content in developing sperm and find that the mature sperm carry a highly distinct small RNA cargo. By biochemical pulldown, we identify a small RNA subset bound directly to piwi protein. And, we show that piRNA-pathway controlled sperm small RNAs are linked to target gene repression in offspring. Critically, we find that full piRNA-pathway dosage is necessary for the intergenerational metabolic and transcriptional reprogramming events triggered by high paternal dietary sugar. These data provide a direct link between regulation of endogenous mature sperm small RNAs and transcriptional programming of complementary sequences in offspring. Thus, we identify a novel mediator of paternal intergenerational epigenetic inheritance.

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Intergenerational programming of hepatic xenobiotic response by paternal Nicotine exposure

Project description:Although it is increasingly accepted that some paternal environmental conditions can influence phenotypes in future generations, it generally remains unclear whether the phenotypes induced in offspring represent specific responses to particular aspects of the paternal exposure history, or whether they represent a more generic response to paternal “quality of life”. To establish a paternal effect model based on a known ligand-receptor interaction and thereby enable pharmacological interrogation of the specificity of the offspring response, we explored the effects of paternal nicotine administration on offspring phenotype in mouse. We show that chronic paternal exposure to nicotine prior to reproduction induced a broad protective response to multiple xenobiotics in the next generation. This effect manifested as increased survival following an injection of toxic levels of either nicotine or of cocaine, was specific to male offspring, and was only observed after offspring were first acclimated to sublethal doses of nicotine or cocaine. Mechanistically, the reprogrammed state was characterized by enhanced clearance of nicotine in drug-acclimated animals, accompanied by hepatic upregulation of genes involved in xenobiotic metabolism. Surprisingly, this protective effect could also be induced by paternal exposure to a nicotinic receptor antagonist as well as to nicotine, suggesting that paternal xenobiotic exposure, rather than nicotinic receptor signaling, is likely to be responsible for programming of offspring drug resistance. Taken together, our data show that paternal drug exposure can induce a protective phenotype in offspring by enhancing metabolic tolerance to xenobiotics in the environment.

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Paternal overdiet drives intergenerational transmission of metabolic disorders through sperm epigenetic alteration [MeDIP-Seq]

Project description:We using a mouse model of paternal famine to simulate famine, our data show that paternal famine increases the susceptibility to metabolic disease in offspring through gametic epigenetic alterations.

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Paternal overdiet drives intergenerational transmission of metabolic disorders through sperm epigenetic alteration [RNA-Seq]

Project description:We used a mouse model of paternal famine to simulate famine, our data show that paternal famine increases the susceptibility to metabolic disease in offspring through gametic epigenetic alterations.

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Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder

Project description:Increasing evidences indicate diet-induced metabolic disorder could be paternally inherited, but the exact sperm epigenetic carrier remains unclear. Here, in a paternal high-fat diet (HFD) mouse model, we revealed that a highly enriched subset of sperm small RNAs (30-34 nt) that derived from the 5â halves of tRNAs (tsRNAs), exhibit changes in both expression profiles and RNA modifications. Injection of sperm tsRNAs from HFD male but not synthetic tsRNAs lacking RNA modifications, into normal zygotes generated metabolic disorders in the F1 offspring. Injection of HFD sperm tsRNAs derails gene expression in both early embryos and islets of F1 offspring, enriched in metabolic pathways, but unrelated to DNA methylation at CpG-enriched region. Collectively, we uncover sperm tsRNAs as a type of âepigenetic carrierâ that mediate intergenerational inheritance of acquired traits. Mature sperm small-RNA profiles between High-fat-diet (HFD) and Normal-diet (ND) males; Transcriptional profiles of 8-cell embryos and balstocysts that developed from zygotes that injected with sperm RNAs from HFD vs ND males. Transcriptional profiles and RRBS profiles of islets of F1 offsrping that generated from zygotes that injected with sperm RNAs from HFD vs ND males.

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Exercise during pregnancy prevents parental obesity-induced decline of metabolic function in adult offspring [Bisulfite-Seq]

Project description:It is known that both maternal and paternal health/disease can influence the early development and later metabolic homeostasis of the offspring. We investigated whether maternal exercise during gestation alone could protect the offspring from the adverse effects of either maternal or paternal obesity induced by high-fat diet (HFD). To understand the underlying mechanisms we performed transcriptomics, whole-genome DNA methylation and targeted DNA methylation analysis at the metabolic master regulator, peroxisome proliferator-activated receptor g coactivator-1a (Pgc-1a) promoter in the adult offspring skeletal muscle. Both maternal and paternal HFD resulted in impaired glucose tolerance in the offspring at 9 months of age. Maternal exercise during gestation completely mitigated this metabolic impairment induced by either maternal or paternal HFD. Adult offspring exposed to either maternal or paternal HFD without exercise during gestation had skeletal muscle transcriptional profiles enriched in genes regulating inflammation and immune responses, whereas maternal exercise resulted in a transcriptional profile that was more similar to control offspring from normal chow fed parents. Changes in promoter and CpG DNA methylation were detected between the groups but did not explain the transcriptional changes. Maternal HFD increased methylation of the Pgc-1α promoter at CpG -260, which was prevented by maternal exercise. Paternal HFD did not affect the methylation of the Pgc-1α promoter. These findings demonstrate the negative consequences of maternal and paternal obesity for the offspring’s metabolic outcomes later in life and the clear benefits of maternal exercise during gestation. The mechanisms involve transcriptional regulation of skeletal muscle likely through multiple types of epigenetic modifications.

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Exercise during pregnancy prevents parental obesity-induced decline of metabolic function in adult offspring [RNA-Seq]

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Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder

Project description:Increasing evidences indicate diet-induced metabolic disorder could be paternally inherited, but the exact sperm epigenetic carrier remains unclear. Here, in a paternal high-fat diet (HFD) mouse model, we revealed that a highly enriched subset of sperm small RNAs (30-34 nt) that derived from the 5’ halves of tRNAs (tsRNAs), exhibit changes in both expression profiles and RNA modifications. Injection of sperm tsRNAs from HFD male but not synthetic tsRNAs lacking RNA modifications, into normal zygotes generated metabolic disorders in the F1 offspring. Injection of HFD sperm tsRNAs derails gene expression in both early embryos and islets of F1 offspring, enriched in metabolic pathways, but unrelated to DNA methylation at CpG-enriched region. Collectively, we uncover sperm tsRNAs as a type of “epigenetic carrier” that mediate intergenerational inheritance of acquired traits.

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