Epigenetic change causes fruit fly babies to inherit diet-induced heart disease

We all know that we should eat fruits and vegetables to keep our heart healthy. But now, scientists are learning that epigenetic changes, or molecular imprints that modify our DNA, can make their children – and even their grandchildren – inherit the negative effects of their poor diet. However, the details behind this heritage – and how to stop it – are unclear.

Scientists at the Sanford Burnham Prebys Medical Research Institute (SBP) have now identified an epigenetic marker and two genes that have caused heart failure in children and grandchildren of fruit flies with heart failure induced by a high-fat diet. Inverting the epigenetic modification or overexpressing the two genes has protected subsequent generations from the negative effects of the heart on their parents' diet. These findings help explain how obesity-related heart failure is inherited and uncover potential targets for treatment. The study was published in Communications of the nature on January 14, 2019.

The obesity epidemic is causing rates of heart failure to rise. Currently, more than 6 million people in the United States are living with heart failure, a number predicted to increase to more than 8 million by 2030, according to the American Heart Association (AHA). The condition occurs when the heart is not able to pump enough blood throughout the body and usually affects people over 65 years.

"Scientists have waited for many years to identify the genetic basis of obesity, but the answers have remained intriguing and indescribable," says Rolf Bodmer, Ph.D., senior author of the study and director and professor of the University's Development, Aging and Regeneration Program . SBP. "Our findings reveal an inheritance mechanism behind heart failure fed by a high-fat diet. We also discovered an epigenetic factor and genetic targets that could be exploited to protect individuals from the poor diet effects of their parents or grandparents."

There is evidence in humans that diet during pregnancy can have lasting effects on children. Babies born after a Dutch famine during World War II had higher rates of obesity and coronary heart disease. Overweight or obese mothers are more likely to have children with diabetes or other health problems. However, studying the underlying genetic and molecular mechanisms that are responsible for these observations has been difficult, hampering scientists' ability to break the inheritance chain.

Fruit flies offer an attractive alternative to studying genetics. Eighty percent of the genes that cause disease in humans are also found in the fly. In addition, its tube-shaped heart consists of only 80 cardiac cells, called cardiomyocytes (in humans, this tube folds in the four chambers of our heart). Its resemblance to humans, simplicity and short life cycle – a new generation is born every fortnight – makes fruit flies an excellent model for studying the genes that contribute to the health of the human heart.

In the study, scientists fed a fly rich in coconut oil for five days. These flies have become overweight and have developed features that mimic human lipotoxic heart disease – the accumulation of fat in cardiac cells – and lead to heart failure, including irregular heartbeat (arrhythmia) and weakened heart contractions. Their children and grandchildren also had cardiac dysfunction, even when receiving a normal diet.

When comparing generations of flies born to parents who consumed normal diets, the scientists identified an inherited epigenetic marker called trimethylated lysine 27 in histone 3 (H3K27me3). Reducing the level of this epigenetic mark along the fruit fly has protected the two subsequent generations of cardiac dysfunction.

The researchers also identified two genes involved in metabolism that were "rejected" in the next two generations of flies, called bmm and PGC-1. Revving up metabolism of flies by overexpressing these genes also protected the hearts of children and grandchildren of flies who ate a fatty diet. This protection lasted even if the subsequent generation consumed coconut oil.

This study provides the proof-of-concept results that scientists need to explore new holdings.

"Next, we want to determine how and when these genetic and epigenetic changes are inherited and to what extent they arise from the mother or father," says Bodmer. "We want to study the development of fruit fly at all stages – from egg to embryo to adulthood – to determine which primary changes are inherited and to what extent these changes are implemented to cause metabolic imbalance and lipotoxic heart disease. we learn to intervene and prevent these changes from passing to the next generation. "

"We would also like to better understand how these two pieces of the puzzle – inherited from the epigenetic and genetic changes – are Epigenetic changes are broad and typically control multiple molecular pathways. A better understanding of the gene networks that are activated and deactivated when eating a high-fat diet and how these changes are orchestrated by epigenetic factors could help us find important therapeutic targets for treat problems related to obesity heart failure. "

Provided by
Sanford Burnham Prebys Medical Discovery Institute