Transcriptome and chromatin landscapes of fasting

Fasting is defined as regular cessation of food intake and can take various forms such as intermittent fasting, time-restricted feeding, ketogenic diets, or fasting-mimicking diet. Different fasting protocols have been shown to harbour many health benefits beyond simple weight loss. In animal models, fasting even led to increased longevity and mitigation of disease symptoms. In humans, fasting is clinically tested as therapy for conditions such as diabetes, nerve and muscle-related disorders, and cancer. Scientifically, the effects of fasting are well described on the level of organs and the molecules that communicate between them (e.g. hormones). In this project we zoom into the nuclei of cells, to define fasting-induced changes on gene activation upon nutrient withdrawal. We further ask the question which of these changes are memorized by the cells to provide the long-term health benefits through fasting. We call this, fasting memory and hypothesise that it is manifested in permanent changes at the DNA level affecting gene regulation. The DNA in the nucleus of a human cell codes for more than 20.000 genes. Which genes are activated at what time defines the function of a cell and its reaction to environmental stimuli like fasting. The activity of the genes of our cells are regulated by proteins called transcription factors. They can bind to DNA, open it up, and enable the activation (transcription) of genes. We investigate the dynamic fasting response of cells that are known to strongly respond to nutrient challenges (liver cells, fat cell, muscle cells) with state-of-the-art omics technologies. Omics technologies are based on DNA sequencing and enable measurement of tens of thousands of genes and DNA features, like openness, in one experiment. Results generated in this project will, for the first time, describe fasting-mediated regulatory mechanisms in a detailed manner on the cellular and DNA level. Thus, the project will advance our fundamental understanding of gene activation mechanisms acutely and permanently reprogrammed through fasting regimens in health and disease. These mechanistic insights harbour the potential of being transformative for the medical application of fasting as a form of therapy.

Gene regulatory networks during fasting Fasting is defined as regular cessation of food intake and can take various forms such as intermittent fasting, time-restricted feeding, ketogenic diets, or fasting-mimicking diet. Different fasting protocols have been shown to harbour many health benefits beyond simple weight loss. In animal models, fasting even led to increased longevity and mitigation of disease symptoms. In humans, fasting is clinically tested as therapy for conditions such as diabetes, nerve and muscle-related disorders, and cancer. Scientifically, the effects of fasting are well described on the level of organs and the molecules that communicate between them (e.g. hormones). In this project we zoom into the nuclei of cells, to define fasting-induced changes on gene activation upon nutrient withdrawal. We further ask the question which of these changes are "memorized" by the cells to provide the long-term health benefits through fasting. We call this, "fasting memory" and hypothesise that it is manifested in permanent changes at the DNA level affecting gene regulation. The DNA in the nucleus of a human cell codes for more than 20.000 genes. Which genes are activated at what time defines the function of a cell and its reaction to environmental stimuli like fasting. The activity of the genes of our cells are regulated by proteins called "transcription factors". They can bind to DNA, make it accessible, and enable the activation (transcription) of genes. We investigate the dynamic fasting response of tissues that are known to strongly respond to nutrient challenges (liver, fat) with state-of-the-art "omics" technologies. Omics technologies, based on DNA sequencing, enable measurement of the activity of tens of thousands of genes and of DNA features, like accessibility, in one experiment. Our results reveal that thousands of genes are being activated by fasting through combinatorial binding of many transcription factors. These novel networks of transcription factors in liver and adipose tissue regulate the acute response to nutrient withdrawal in a concerted manner. In particular, nuclear receptors, gene regulatory proteins that can be activated by ligands, emerge as key regulators during fasting. Cyclic repetition of fasting regimens blunts some of the transcriptional responses to acute fasting, suggesting an underlying adaptive process. Further studies could focus on utilizing these findings by developing such nuclear receptor ligands as fasting-mimicking drugs, that can improve compliance and efficacy of fasting to improve metabolic health.