Epigenetic Inheritance S1

Paternal pre-conception nutrition has been associated with metabolic dysfunction in the offspring of several animal species. A likely mechanism contributing to this phenomenon is epigenetic inheritance. Several research groups, including ours, have shown that environmental factors, such as diet, physical activity and metabolic condition, can alter the epigenetic information carried in spermatozoa. Since the epigenetic signature of gametes plays an important role in embryonic development, we hypothesize that nutrition-induced changes of the sperm epigenome can modulate health of the next generation offspring. While the underlying mechanisms of epigenetic inheritance show broad evolutionary conservation, the specificity of epigenetic responses to nutritional challenge in different species remains unknown.
Among selected animal species, we are using the mini pig as a representative model of human obesity and whole-body metabolism and aim to determine the impact of a chronic Western-style dietary intake on the epigenetic programming of spermatozoa. Young, sexually mature male mini pigs are exposed to a 3-month dietary intervention of either a control diet or high-caloric Western-style diet, and semen samples are collected at different time points during the intervention. A washout period of the diets is followed to examine if nutrition-induced epigenetic variation in sperm is reversible. Isolated spermatozoa are examined for alterations in their epigenetic signature and downstream gene set enrichment analysis is performed to determine molecular pathways affected by the differential dietary intakes.


Western diet effects on metabolism and epigenetic reprogramming of spermatozoa in mini pigs

Diet impacts all aspects of health, including behaviour and reproduction. Obesogenic diets have been linked to increased anxiety in rodent models comparing effects of control to treatment “high-fat/Western” diets. Although the behavioural differences have been interpreted as a consequence of high fat, multiple components of the diets differ in a two-diet design, and therefore it is not clear whether fat is to blame. Inspired by ecological experimental designs, Nutritional Geometry uses a multi-dimensional framework to unpack individual and interactive effects of dietary components on health outcomes. We fed male C57Bl6 mice one of ten different isocaloric diets differing in macronutrient balance from 5 to 15 weeks of age, and assessed risk-taking behaviour using an Elevated-Plus maze. Treatment males were then mated to chow-fed females, and offspring raised on a chow diet. At 15 weeks of age, offspring behaviour was assessed using the Elevated-Plus maze. No influence of dietary fat was found on male risk-taking behaviour, rather, time spent in the closed arms was determined by an interactive effect between dietary protein and carbohydrates. Males fed low-protein, high-carbohydrate diets spent the most time in closed arms, indicating increased anxiety. Male offspring of these anxious fathers also showed increased anxiety, although the pattern of movement around the maze differed from their fathers. Epigenetic analyses of sperm and offspring tissues is currently underway to explore mechanisms driving these changes in offspring.

Intergenerational effects of dietary macronutrient balance on male mouse risk-taking behaviour

Most rodent dietary studies compare effects of a ‘high-fat diet’ versus a control. These two diets often differ in calorie and protein content, making it difficult to determine what aspect of the diet is responsible for changes observed. 

Nutritional Geometry provides an alternative and multi-dimensional framework to examine how macronutrient balance affects health. Here we examine effects of dietary macronutrient balance on body length and fasting blood glucose in young adult male mice and their female offspring.

Using the nutritional geometry framework, we identify that dietary fat is negatively associated with body length and fasting blood glucose levels in adolescent males. Further, females sired from males exposed to the differential diets exhibited contrasting effects to those observed in fathers, with paternal dietary fat intake being positively associated with female offspring body length and fasting blood glucose in some instances. 

Results from this study highlight the indirect inheritence of phenotypes from fathers to daughters on the parameters of body size and blood glucose, along with suggesting the importance of caloric load versus macronutrient makeup on inherited effects.

Macronutrients have differential effects on anthropometry and metabolic health in male mice and their daughters

**Session Chair:** Professor Romain Barrès, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen   

**Speaker**: Professor Isabelle Mansuy, Medical Faculty, University of Zurich & Department of Health Science & Technology, ETH Zurich   

![](https://assets.underline.io/uploads/markdown_image/1/image/13e6908c3f561271de6c00352079e05d.png)  
Isabelle Mansuy holds a Ph.D. in developmental neurobiology from the University Louis Pasteur in Strasbourg, France for a doctoral thesis conducted at the Friedrich Miescher Institute in Basel. She trained as postdoctoral fellow in the lab of Eric Kandel at the Center for Learning and Memory at Columbia University in New York and established her own lab as assistant professor in neurobiology at ETH Zurich in Dec 1998. I. Mansuy initially conducted research in molecular cognition and made landmark discoveries on the mechanisms of forgetting in mammals. At the same time, she progressively changed field and redirected her research towards epigenetic inheritance, that recently emerged as a new discipline. Her lab is one of the pioneers in the field, and contributed to the current paradigm shift about the epigenetic basis of heredity. I Mansuy lab studies the epigenetic mechanisms underlying the heritability of traits induced by environmental exposure in early life. It showed in experimental mice that traumatic stress in postnatal life alters behavior, physiology and metabolism across several generations, and that inheritance of these symptoms depends on epigenetic factors in germ cells, particularly sperm RNA. The discovery establishes the existence of a RNA-based form of heredity in mammals independent from the DNA sequence, similarly to that known in plants and invertebrates. The fundaments of these findings in mice have been in part validated by translational analyses in trauma patients in humans. This research provides important advances on the epigenetic regulation of body functions and new knowledge about heritable chronic environmental diseases, that may promote the development of diagnostic and therapeutic treatments in the future. I. Mansuy co-authored >150 research articles, reviews and book chapters in neurosciences and neuroepigenetics. She published a book on epigenetics for the pay public translated in French and German “Reprenons le contrôle de nos gènes”, Larousse (April 2019) and “Wir können unsere Gene steuern” Berlin Verlag (Aug 2020). She is active in multiple scientific and research funding boards, and is member of the Swiss Academy of Medical Sciences, the European Academy of Sciences (EURASC), and the European Molecular Biology Organization. She is Knight in the National Order of Merit and in the Legion of Honor in France.

**Short talk**: Dr. Congru Li, Postdoc, Karolinska Institute

**Short talk**: Dr. Virender Rehan, Professor, Harbor UCLA Medical Center-David Gaffen School of Medicine

technical paper

**Epigenetic Inheritance across species**

We are happy to invite you to register for the GECKO Conference – inspired by the Gametic Epigenetics Consortium Against Obesity (hence, GECKO). Professor Romain Barrès Head of the GECKO Consortium, and his research group will be hosting the conference, which will take place virtually between **May 25-28, 2021**. **Sessions will be live daily from 8.00-10.30 and 17.00-19.30 CET.**

The theme of the conference is intentionally broad. We will have sessions dedicated to the technical aspects of studying epigenetic inheritance, how we can use a comparative approach to understand inheritance mechanisms, the evolutionary explanations for epigenetic inheritance and a session focused on how our research could influence reproductive biology. 

We already have a fantastic line-up of speakers, including Noora Kotaja (University of Turku), Qi Chen (University of California), Michael Wilson (University of Toronto), Isabelle Mansuy (University and ETH Zurich), Oliver Rando (University of Massachusetts), Anita Öst (Linköping University) and Tobias Uller (Lund University).

The conference format will include panel discussions, short talks selected from submitted abstracts, poster sessions and a set of short and sharp talks to accompany these.

The deadline for submitting an abstract to be considered for a talk or poster is **May 4th .** 
Those selected to present will be informed in the following week, with **final posters due May 17th .**
![](https://assets.underline.io/uploads/markdown_image/1/image/ea7614ef58a8f691e8295529020987ea.png)
[![](https://assets.underline.io/uploads/markdown_image/1/image/6b2bc323e45f696b7cd29d1650a5e2cc.jpg)](https://zmxuhia1.paperform.co/)

![](https://assets.underline.io/uploads/markdown_image/1/image/ea7614ef58a8f691e8295529020987ea.png)

[![](https://assets.underline.io/uploads/markdown_image/1/image/ac0bcdd33edcb55782729d3b03c29bdc.png)](https://drive.google.com/file/d/1AzPiQQYPvStIzAApkEk4AqejZs6HHhEc/view?usp=sharing)

### ** Program at a Glance **
![](https://assets.underline.io/uploads/markdown_image/1/image/17617a252626cfe73fc1a894e7d68ab1.png)
![](https://assets.underline.io/uploads/markdown_image/1/image/ea7614ef58a8f691e8295529020987ea.png)


# About GECKO

The Gametic Epigenetics Consortium Against Obesity (GECKO) is a research consortium funded by a Novo Nordisk Foundation Challenge grant from 2019 to 2025. The main goal of the consortium is to understand the effect of diet on the epigenetic signatures that are passed through sperm to offspring, and the effect these signatures have on the developing offspring and future generations. 

The GECKO is comprised of three leading research groups headed by Professor Romain Barrès at the University of Copenhagen, Professor Stephen Simpson at the University of Sydney and Professor Marcelo Nobrega at the University of Chicago.



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Find out more information and register to the event **for free** by making an account in Underline.

Romain Barrès

4

Presentations

Epigenetic Inheritance S1

Western diet effects on metabolism and epigenetic reprogramming of spermatozoa in mini pigs

Intergenerational effects of dietary macronutrient balance on male mouse risk-taking behaviour

Macronutrients have differential effects on anthropometry and metabolic health in male mice and their daughters

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