Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Paternally induced transgenerational inheritance of susceptibility to diabetes in mammals (MeDIP-Seq)

ABSTRACT: The global prevalence of type 2 diabetes (T2D) is increasing, and it is contributing to the susceptibility to diabetes and its related epidemic in offspring. Although the impacts of paternal T2D on metabolism of offspring have been well established, the exact molecular and mechanistic basis that mediates these impacts remains largely unclear. Here we show that paternal T2D increases the susceptibility to diabetes in offspring through the gametic epigenetic alterations. Paternal T2D led to glucose intolerance and insulin resistance in offspring. Relative to controls, offspring of T2D fathers exhibited altered gene expression patterns in the pancreatic islets, with downregulation of several genes involved in glucose metabolism and insulin signaling pathway. Epigenomic profiling of offspring pancreatic islets revealed numerous changes in cytosine methylation depending on paternal T2D, including reproducible changes in methylation over several insulin signaling genes. Paternal T2D altered overall methylome patterns in sperm, with a large portion of differentially methylated genes overlapped with that of pancreatic islets in offspring. Our study revealed, for the first time, that T2D can be inherited transgenerationally through the mammalian germline by an epigenetic manner. Examination of the effect of paternal T2D on the DNA methylation in the pancreatic islets of offspring and in the sperm of father.

ORGANISM(S): Mus musculus

SUBMITTER: yanchang wei

PROVIDER: E-GEOD-43238 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The global prevalence of type 2 diabetes (T2D) is increasing, and it is contributing to the susceptibility to diabetes and its related epidemic in offspring. Although the impacts of paternal T2D on metabolism of offspring have been well established, the exact molecular and mechanistic basis that mediates these impacts remains largely unclear. Here we show that paternal T2D increases the susceptibility to diabetes in offspring through the gametic epigenetic alterations. Paternal T2D led to glucose intolerance and insulin resistance in offspring. Relative to controls, offspring of T2D fathers exhibited altered gene expression patterns in the pancreatic islets, with downregulation of several genes involved in glucose metabolism and insulin signaling pathway. Epigenomic profiling of offspring pancreatic islets revealed numerous changes in cytosine methylation depending on paternal T2D, including reproducible changes in methylation over several insulin signaling genes. Paternal T2D altered overall methylome patterns in sperm, with a large portion of differentially methylated genes overlapped with that of pancreatic islets in offspring. Our study revealed, for the first time, that T2D can be inherited transgenerationally through the mammalian germline by an epigenetic manner. For all comparisons shown, male F0 founders were weaned from mothers at 3 weeks of age, and sibling males were put into cages with high-fat diet (33% energy as fat) or control diet until 12 weeks of age, at which point mice fed with HFD were injected intraperitoneally with a low dose of STZ and kept on the same diet for 4 weeks. Fasting blood glucose was examined each week post-STZ for 4 weeks, and only glucose level at 7~11 mM was considered as type 2 diabetes. Females were always raised on standard diet. At 16 weeks, male F0 founders were mated with females. After 1 or 2 days, males were removed, and pregnant females were left alone until their litters were 3 weeks of age. Note that we always used virgin females to avoid confounding effects brought about by the females. At 3 weeks of age a portion of the offspring were sacrificed and islets were generated, each from an independent father.Samples from six control and six paternal type 2 diabetes offspring were chosen for microarray analysis.

Project description:Slimming is globally prevalent especially in young women, and it may contribute to the metabolic health of their offspring. Whereas some Lamarckian ideas about environmental inheritance have been dismissed, increasing evidence suggest that certain acquired traits can be transmitted to the next generation. It is therefore of great interest to determine how and to what extent a maternal lifestyle change contributes to their offspring. Here we show that enriched environment (EE) induced maternal slimming improves general health and reprograms metabolic gene expression in mice offspring. EE in mothers induced decreased body weight, adiposity, and improved glucose tolerance and insulin sensitivity. Relative to controls, their offspring exhibited improved general health such as reduced fat accumulation, enhanced metabolic parameters as well as glucose tolerance and insulin sensitivity. Maternal slimming altered the expression of 1,732 genes in the liver of offspring, with coherent downregulation of genes involved in lipid and cholesterol biosynthesis. Epigenomic profiling in offspring revealed numerous changes in cytosine methylation depending on maternal slimming, including hypermethylation of several genes involved in lipid biosynthesis, correlated with the downregulation of these genes. Maternal slimming also altered overall transcriptome patterns in mature oocytes, which contributes largely to the metabolic health and gene expression patterns in offspring. Overall, our studies suggest that maternal slimming have a beneficial role in regulating metabolic profiles in offspring, implying that it might be considered as a potential strategy to reverse the global prevalence of obesity and related metabolic syndromes. Examination of the effect of 2 different maternal lifestyles, control and slimming, on the mRNA expression in the mature oocytes of the female mice. Naturally ovulated mature oocytes (MII stage) were collected from 3 control and 3 slimming female F0 founders (3 oocytes per mouse, 9 oocytes for each group).

Project description:Pancreatic cancer is the 3rd most prevalent cause of cancer related deaths in United states alone, with over 55000 patients being diagnosed in 2019 alone and nearly as many succumbing to it. Late detection, lack of effective therapy and poor understanding of pancreatic cancer systemically contributes to its poor survival statistics. Obesity and high caloric intake linked co-morbidities like type 2 diabetes (T2D) have been attributed as being risk factors for a number of cancers including pancreatic cancer. Studies on gut microbiome has shown that lifestyle factors as well as diet has a huge effect on the microbial flora of the gut. Further, modulation of gut microbiome has been seen to contribute to effects of intensive insulin therapy in mice on high fat diet. In another study, abnormal gut microbiota was reported to contribute to development of diabetes in Db/Db mice. Recent studies indicate that microbiome and microbial dysbiosis plays a role in not only the onset of disease but also in its outcome. In colorectal cancer, Fusobacterium has been reported to promote therapy resistance. Certain intra-tumoral bacteria have also been shown to elicit chemo-resistance by metabolizing anti-cancerous agents. In pancreatic cancer, studies on altered gut microbiome have been relatively recent. Microbial dysbiosis has been observed to be associated with pancreatic tumor progression. Modulation of microbiome has been shown to affect response to anti-PD1 therapy in this disease as well. However, most of the studies in pancreatic cancer and microbiome have remained focused om immune modulation. In the current study, we observed that in a T2D mouse model, the microbiome changed significantly as the hyperglycemia developed in these animals. Our results further showed that, tumors implanted in the T2D mice responded poorly to Gemcitabine/Paclitaxel (Gem/Pac) standard of care compared to those in the control group. A metabolomic reconstruction of the WGS of the gut microbiota further revealed that an enrichment of bacterial population involved in drug metabolism in the T2D group.

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Paternally induced transgenerational inheritance of susceptibility to diabetes in mammals (MeDIP-Seq)

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