“Those chemical modifications that decorate [histones] and modify gene expression — they’re metabolites, full stop,” said Finley, the cancer biologist. “Chemical modifications themselves are metabolites, and their removal is dependent on metabolites.”

Fifteen years ago, when Kathryn Wellen was a postdoc studying cancer cells, she discovered that the epigenetic marks on histones change in response to the presence of nutrients. When food is plentiful, mitochondria make a metabolite called acetyl-CoA. It diffuses into the nucleus, where the genome resides, through large pores. There, enzymes break down the metabolites into epigenetic marks known as acetyl groups and place them on histones to activate one set of genes. However, when the cells are starving, enzymes strip off the acetyl groups. Some of those acetyl groups are turned back into acetyl-CoA and consumed for energy, while others are recycled to activate a different set of genes.

Clearly there’s a lot of metabolic activity occurring in the nucleus. Wellen wondered whether the nucleus had its own unique metabolism and could therefore be considered a “metabolic compartment.” Working with Nate Snyder, a biochemist at the Lewis Katz School of Medicine at Temple University, Wellen and other researchers developed new methods to measure metabolites in different parts of the cell and saw that metabolic activity in the nucleus is not identical to activity occurring elsewhere.

“Although that may sound obvious, it was not,” Wellen said. The nucleus’s metabolic activity was specific to the functions in that compartment, including epigenetic activity. “There are a lot of metabolic enzymes that are actually in the nucleus and are dynamically regulated in the nucleus,” said Wellen, who now heads a lab at the University of Pennsylvania. “We were really excited to find that.”

This idea of the nucleus as a metabolic compartment was foundational to understanding how metabolism impacts embryonic development. In early embryonic cells, as developmental decisions are made that direct cells to become ectoderm, mesoderm and endoderm, all of the epigenetic marks on the histones get repositioned. They can be removed, added and relocated to activate certain genes and repress others.

“What is intriguing is that all of this is associated with a massive accumulation of metabolic enzymes in the nucleus,” said Żylicz, the developmental biologist. These enzymes make molecules, which then activate other enzymes that remove epigenetic marks and lay down new ones as cells grow, divide and take on different fates.

During this period, the cell moves many enzymes from the cytoplasm and mitochondria to the nucleus. That way, the metabolites necessary for gene activity can be produced locally, in the nucleus, where they are needed, Żylicz said. “The moment where you reprogram the epigenome — that happens to be the same time when you’re also really using this nucleus as a metabolic compartment.”

Early in human development, the embryo is a ball of cells. The cells on the outside form the placenta; the cells on the inside form the embryo. The major difference between these two types of cells is in the activity of metabolic genes. Recently, Żylicz’s team pinpointed differences between these cells in alpha-ketoglutarate, a well-studied metabolite, and showed that the metabolite accelerated the differentiation of stem cells into cells that will become the placenta.

Alpha-ketoglutarate not only controls differentiation in stem cells; it does the same in cancer cells, Finley’s team and other groups found a few years ago. They were studying p53, a protein that is well known for its anticancer effects; its gene is the most commonly mutated gene in human cancer. Their study, published in Nature, found that p53 caused alpha-ketoglutarate to accumulate; this alpha-ketoglutarate altered the fate of the cancer cells so that they were less likely to form tumors. This was striking and unexpected because researchers had assumed that p53 has an anticancer effect by directly regulating the activity of genes. It also works by altering metabolism.

“This is particularly exciting because if changing metabolism can change cell fate in a meaningful way, there is the possibility that you might be able to manipulate that therapeutically, where aberrant decisions of differentiation are causal for the disease — like in many forms of cancer,” said Rutter, who was not involved in the study.

In some ways, this interplay between metabolism and genes is obvious: We know that life is influenced by both its genes and its environment. This new, exciting field of research shows at a molecular level how the materials available to our cells influence their fates, and ours.