Paternal RNA-mediated epigenetic inheritance of metabolic disorders: impact of weight loss on the human sperm epitranscriptome
Increasing evidence suggests that several non-communicable diseases, including obesity and its associated metabolic disorders, are inherited from parents to offspring over several generations by non-genetic mechanisms.
In this context, it has been suggested that parental environmental cues might induce epigenetic modifications in the germ line, which are transmitted to the progeny. Hence, etiological and risk factors that contribute to the insurgence of non-communicable diseases have the potential to drive the development of pathology(ies) in the progeny.
Fundamentally, the role of sperm RNA in epigenetic inheritance is not a new phenomenon and has been largely addressed in experimental models. Yet, validation in humans is quite challenging. By combining clinical trial methodology, advances in rodents and cutting-edge computing technologies in bioinformatics, we can rise to this challenge. That is the main objective of our project.The identification of the sperm epitranscriptomic signature in obese men relative to non-obese men will therefore not only provide new insights into the molecular mechanisms involved in the epigenetic inheritance of obesity in human, but also will aid the identification of new loci potentially involved in the development of metabolic pathologies. The identification of loci involved in the development of obesity is pioneering and challenging. However, if we are able to implement this ambitious project, we could give numerous insights into the nature of the mechanisms that modify the transcriptomes such a way they become able to encode and transfer complex phenotypic changes to the progeny and then counteract the development of obesity around the world. Furthermore, we might be able to identify biomarkers of environmentally-induced epigenetic perturbation.
On the other hand, by performing microinjection of human RNA into mouse embryos, we hope to determine the role of human sperm RNA in epigenetic inheritance. This is, of course, very challenging and high risk. However, if we manage to demonstrate the role of human RNAs through these experiments, we will open new avenues in the identification of genes involved in the development of obesity and its associated diseases.
This work will contribute to a better understanding of the molecular mechanisms involved in the non-genetic inheritance of obesity in human, and to the identification of obese-susceptibility loci whose expression can be modulated by environmental factors and consequently induce the development of the disease in successive generations.
|Institut d'Investigació Biomèdica de Girona
|Institute of Pharmacy and Biochemistry
Our consortium has now developed the protocol to analyze the epitranscriptome modification from human sperm samples. We have included 40 non-obese and 50 obese patients.