MEDICINE AND HEALTH

Scientists have solved the mystery of the intergenerational inheritance of diabetes on the origin of eggs It provides a new perspective for the understanding and prevention and control of chronic diseases such as diabetes


On May 18, Nature published the latest results of the collaborative research of Huang Hefeng, academician of the Chinese Academy of Sciences, key laboratory of reproductive genetics of the Ministry of Education (Zhejiang University) and professor of the Institute of Reproduction and Development of Fudan University, and Xu Guoliang, academician of the Chinese Academy of Sciences and researcher of the Center for Excellence in Molecular Cell Science of the Chinese Academy of Sciences.

This study confirms the origin of oocytes of diabetes, reveals for the first time the precise regulatory mechanism of epigenetic methylation in the intergenerational transmission of egg-derived diabetes, analyzes the insufficient insulin secretion of offspring of oocyte mother (Tet3) to regulate the genetic characteristics of paternal parents, and realizes the intergenerational inheritance of diabetes susceptibility, providing a new scientific perspective for human understanding and prevention and control of adult chronic diseases such as diabetes.

“Mother-infant disease”: maternal germ cells mediate the transmission effect of diabetes

In the 1990s, the British scholar Barker proposed that the incidence of chronic diseases such as diabetes and hypertension increased due to adverse environmental exposures in the intrauterine period (fetal stage), which provided a new idea for the pathogenesis of adult chronic diseases.

The development of Barker’s theory contributed to the importance of environmental exposure during pregnancy for the health of the offspring.

“At present, clinically, this type of chronic diseases such as metabolism and cardiovascular diseases that originated early in life are generally referred to as developmental diseases.” Huang Hefeng told China Science Daily, “This is a late-onset birth defect, which has far-reaching and widespread impact, brings a heavy burden to society and families, and seriously affects the health of our population.” ”

As one of the earliest teams in the world to carry out research on developmental diseases, Huang Hefeng’s research group has long been committed to the study of the pathogenesis mechanism of adult diseases caused by exposure to environmental factors during maternal pregnancy, which for the first time confirmed that intrauterine high glucose exposure during pregnancy can change the intergenerational/intergenerational inheritance caused by DNA methylation, and found that the origin of the disease can be moved forward to pregestception (gamete development), and took the lead in proposing the theory of “gamete-derived adult disease” in the world. However, compared with direct exposure of the fetus during pregnancy, how gametes or germ cells transmit adverse environmental factors to offspring has not been elucidated.

Based on this problem, Huang Hefeng’s research group cooperated with Xu Guoliang’s research group, on the basis of previous research, after continuous exploration, they took pre-pregnancy diabetes as the starting point, and finally discovered the transmission effect of female eggs that can mediate diabetes, found the key to opening the oval intergenerational inheritance model – DNA demethylase Tet3, and explained the regulatory pathways and specific ways of Tet3-mediated intergenerational inheritance.

Diabetes is one of the chronic diseases affecting human health, its incidence is high and the incidence is hidden, and about 2/5 of women with diabetes worldwide are of childbearing age. Taking pregestal diabetes as an example, the research team established a streptouradlin-induced mouse model of diabetes, obtained diabetic mouse oocytes and normal male rat sperm for in vitro fertilization, and implanted the early embryos formed in vitro into the uterus of normal surrogate mother mice to continue development. After excluding the interference of high glucose environment during pregnancy and postpartum, it was found that the glucose tolerance of the first generation of mice was impaired, mainly manifested by insufficient insulin secretion, while the second generation of mice did not have obvious glucose tolerance abnormalities. It shows that oocytes have been branded with metabolic abnormalities before pregnancy, and transmission to offspring triggers intergenerational inheritance of diabetes.

Scientists crack the mystery of intergenerational inheritance of diabetes on the origin of eggs - Huang Hefeng, Chinese Science Journal, revised (1) 1055.png

Experimental design and subgeneration of the main phenotypic diagram Courtesy of the interviewee

“Falling out of the water”: Finding the intergenerational genetic key to egg-derived diabetes

Epigenetics play a bridging role between environmental factors and susceptibility to disease. Using oocyte transcriptome sequencing and validating epigenetic regulatory tool enzymes one by one, the researchers found that dna demethylase, which is also a maternal effector, in the eggs of diabetic mice, decreased significantly.

Xu Guoliang’s research group has revealed the role of Tet3 in egg cell reprogramming: the maternal factor Tet3 derived from egg cells is responsible for the oxidative modification of the parent genome DNA cytosine methyl group, thereby initiating DNA demethylation. This study concludes that oocyte-derived intergenerational inheritance provides direction, and this study further confirms that after in vitro fertilization of oocytes derived from hyperglycemic mice, Tet3 expression in the male nucleus of fertilized eggs decreases and the level of genomic methylation changes.

Islet whole genome methylation sequencing of child fetus mice shows hypermethylation of DNA in the promoter region of glucose kinase (Gck), an important rate-limiting enzyme associated with insulin secretion. The validation of Tet3 knockout mice showed that after Tet3 gene knockout in the oocyte stage, mice had hypermethylation, decreased expression and glucose tolerance in the Gck promoter region. Back-up Tet3 significantly restores methylation levels and impaired offsize glucose tolerance.

This suggests that Tet3 plays a key epigenetic regulatory role in the transmission effects of hyperglycemia oval-derived diabetes.

Scientists crack the mystery of the intergenerational inheritance of diabetes on the origin of eggs - Huang Hefeng, Chinese Science Journal, revised (1) 1552.png

Intergenerational genetic indication of egg-derived diabetes mellitus Courtesy of respondents

“Don’t have a hole in the sky”: The metabolic imprint of the egg is transmitted by the father’s gene

Interestingly, although the eggs experience high sugar exposure, the target gene for Tet3 to affect offspring is not a maternal gene, but a paternal gene.

In order to verify the source and inheritability of the methylation pattern change of the offspring, the research team took the target gene Gck as an example and found that the hypermethylation of the Gck promoter originated from the androgen nucleus of the fertilized egg and could continue to the islets of the offspring adult mice as they developed.

“When distinguishing between the parent and maternal sources of hypermethylation of the Gck gene, it was found that in both blastocysts and offspring islets, the insulin secretion gene exhibited paternal-specific hypermethylation.” Dr. Bin Chen, one of the co-first authors of the paper and a doctor at the Key Laboratory of Reproductive Genetics of the Ministry of Education (Zhejiang University), explains, “This result reveals that after hyperglycemia exposure, the hypermethylation of insulin secretion genes originates from the paternal genome and is passed on to the offspring. ”

What is more noteworthy is that the GV stage oocytes and blastocysts of clinical diabetic patients who were also collected by the research team at the reproductive centers of many hospitals in Shanghai and Zhejiang also showed a trend of decreased Tet3 expression and a state of hypermethylation in the Gck promoter region, which suggested that the research team’s findings in mouse models had clinical significance and brought possibilities for clinical guidance and application.

This discovery deepened people’s understanding of developmentallyogenic diseases, not only for the first time after excluding pregnancy interference, directly looked at the intergenerational genetic role played by eggs as a transmission carrier, but also outlined Tet3 as a decryption key from the molecular perspective, opened a unique paternal genetic route, and achieved a major breakthrough in the research of developmental adult diseases.

At present, the epidemic trend of chronic diseases such as hypertension and diabetes is increasing, and the health management and treatment of patients for a long time has occupied a lot of public health resources, and society has to deal with the heavy burden brought by such high-incidence diseases.

Huang Hefeng said: At present, the prevention effect of chronic diseases in adulthood is not ideal, forcing us to find another way and seek breakthroughs from new angles. A series of developmental disease research results, including this study, have enlightened us that we should fully understand the possibility and importance of intervention early in life, give full attention to young men and women and the maternal and infant period, and fundamentally change the thinking of disease prevention and control, which may be pragmatic and effective for the prevention of chronic diseases.

“This also coincides with China’s medical wisdom of ‘healing the disease before it’s too late’ since ancient times.” Huang Hefeng said, “This research provides a key theoretical basis for the concept of early intervention in life, which is an important premise for our next clinical research and practice, and the research results are expected to become a classic example of clinical transformation and application, which provides a new perspective and strategy for early management of time, development of the source of prevention and control of chronic diseases, reduction of birth defects, and improvement of population health in China.” (Source: China Science Daily, Zhang Shuanghu, Cui Xueqin, Huang Xin)

Related paper information:https://doi.org/10.1038/s41586-022-04756-4



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