hyperglycemic-epigeneticsWhat if stress experienced by fathers could actually be passed down epigenetically to their children, who then experience its effects later in life? Previous research has hinted that, in mice, trauma experienced by a father leaves epigenetic marks on his sperm RNA, which is inherited by his offspring who later express the same depressive behaviors as their dad. Also, another study that investigated the devastating Quebec Ice Storm of 1998 has suggested that prenatal maternal stress could trigger distinct DNA methylation signatures in ice storm babies. And now evidence for intergenerational epigenetic inheritance continues to mount as a new study links stress in mice fathers to increased high blood sugar in their offspring due to the epigenetic modification called DNA methylation. A group of researchers in China, including those from Shanghai Jiao Tong University School of Medicine, Rui-Jin Hospital, and Hubei Polytechnic University School of Medicine, recently published their supportive research in Cell Metabolism.
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Co-senior author and endocrinologist at the Shanghai Jiao Tong University School of Medicine and Rui-Jin Hospital, Xiaoying Li, explained, “We are very interested in how behavioral change affects glucose homeostasis. Epidemiological studies have demonstrated the association of psychological stress with incident diabetes. We are curious about whether the effect can be passed down through generations.”

First, Li and her colleagues induced stress on male mice by confining them in plastic tubes for 2 hours a day for a total of 2 consecutive weeks. After, they discovered that the glucose levels of the mice rose, yet they gained weight more slowly. In their blood, stress hormones known as glucocorticoids rose. When the scientists mated the stressed male mice with normal females, their babies had elevated blood glucose levels as well.

The cause of the spike in blood sugar was linked to the gene Sfmbt2. The extra glucocorticoids led to the addition of methyl groups to Sfmbt2 in the fathers’ sperm. This epigenetic process is termed DNA methylation, defined as the transfer of methyl groups onto DNA via enzymes known as DNA methyltransferases (DNMTs), which impacts gene expression without altering the underlying genetic sequence. Increased DNA methylation patterns of the Sfmbt2 promoter changed the expression of Sfmbt2 and the intronic microRNA-466b-3p.

Not only did the group of researchers detect the epigenetic change brought on by psychological stress experienced by the fathers in their sperm, but the altered methylation of the Sfmbt2 promoter was also detected in the livers of their offspring. Specifically, the researchers used methylated DNA immunoprecipitation (MeDIP) followed by qPCR (MeDIP-qPCR) and pyrosequencing analysis to show that the captured methylation of the Sfmbt2 promoter was enhanced.

Xuejin Chen, the other senior co-author at the Shanghai Jiao Tong University School of Medicine, said, “The epigenetic reprogramming from stress, through glucocorticoids, was surprising.”

The intronic microRNA-466b-3p in Sfmbt2 assists in the regulation of an enzyme known as phosphoenolpyruvate carboxykinase (PEPCK). PEPCK is involved in regulating the production of glucose in the liver. However, when mammals reproduce, Sfmbt2 is turned off in the oocyte, or egg, of the mother, so the father passes down the one working copy from his sperm to his child. When the only functional Sfmbt2 gene has these epigenetic tags on it, in other words, when it is overly methylated, the intronic microRNA-466b-3p is silenced. This means PEPCK is not regulated as it normally should be, causing the offspring’s livers to produce an excess of PEPCK. This, ultimately, leads to a spike in their blood glucose levels.
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Learning more about these mechanisms and how DNA methylation of certain genes may impact blood sugar levels of offspring can aid in the development of new treatments. The researchers were able to block the impact glucocorticoids had on the sperm by injecting the mouse fathers with a chemical that reduces the effect of these stress hormones. In doing so, the team was able to prevent the increased methylation of the Sfmbt2 gene.

Li believes the insight gained from their epigenetic mouse study may one day be able to help treat people who are hyperglycemic. Although future research has a long way to go to apply these concepts to human therapies, these studies continue to open new doors to potential epigenetic treatments.

Bailey Kirkpatrick

Source: Wu, Lu, and Jiao et al. (2016). Paternal Psychological Stress Reprograms Hepatic Gluconeogenesis in Offspring. Cell Metabolism, In press.

Reference: Cell Press. Stressed mouse dads give their offspring high blood sugar. EurekAlert. 18 Feb 2016. Web.

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