Pluripotent stem cells burn a nutrient called betaine to fuel their metabolism, and a gene called Spic controls this process. When Spic is missing, the cells lose their identity and start differentiating too early. This matters because scientists do not understand how a cell’s metabolism talks to its epigenome—the chemical tags on DNA that switch genes on or off. The link is critical: during early development, cells must coordinate their energy use with their gene expression programs. Disruptions in one-carbon metabolism, the pathway betaine feeds into, are linked to neurodevelopmental disorders in newborns, yet the molecular steps remain unknown. If this research succeeds, it will reveal the first genome-wide map of a specific chromatin modification called H3R17me2a in pluripotent stem cells and show how betaine metabolism controls it. That knowledge could improve culture media for stem cell therapies and IVF. It may also explain how maternal vitamin deficiencies or metabolic mutations cause birth defects—and whether betaine supplementation, already used in some newborn treatments, can rescue those defects. This is fundamental science. It does not promise a near-term treatment. But understanding how metabolism shapes cell identity in the embryo could eventually guide interventions for metabolic disorders that begin before birth.
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During early development, pluripotent stem cells have a remarkable ability to differentiate into any specialized cell type in the body. As these cells differentiate, they change how they use food and make energy, a process called metabolism. Metabolic pathways supply essential metabolites for chemical modifications of chromatin, ultimately affecting gene expression. However, there is a fundamental gap in our knowledge about the molecular mechanisms through which cell metabolism affects chromatin modifications in pluripotent stem cells and how these processes are coordinated during early development. Understanding these mechanisms is important for comprehending normal development and can provide new insights into certain diseases associated with faulty metabolism in newborns. We recently discovered that pluripotent stem cells have an unusual metabolism and, unlike adult cells, use a specific nutrient called betaine to drive their metabolism. Notably, betaine participates in a specific biochemical pathway called one-carbon metabolism, which produces key chemicals involved in chromatin modification. We also found that this unusual betaine metabolism is activated by a gene called Spic, leading to elevated levels of a specific chromatin modification called H3R17me2a. We have noticed that the level of Spic and the activity of betaine metabolism decrease rapidly during stem cell differentiation. In addition, we observed that in the absence of Spic, pluripotent cells cannot maintain proper chromatin modifications, resulting in premature stem cell differentiation. These observations lead us to hypothesize that betaine metabolism plays an important role in controlling cell identity in pluripotent stem cells. Thus, this proposal aims to investigate the molecular mechanisms through which Spic and betaine metabolism control the metabolic-epigenetic crosstalk in pluripotent stem cells. Firstly, we will determine whether pluripotent cells are able to function normally when betaine metabolism is blocked. These experiments will uncover the functions of betaine metabolism in regulating gene expression, self-renewal, and differentiation in pluripotent stem cells. Secondly, we will investigate the molecular steps by which Spic and betaine metabolism control the genomic deposition of H3R17me2a. While H3R17me2a has been associated with pluripotency in the early embryo, its precise role remains unknown. These experiments will provide the first genome-wide characterization of H3R17me2a in pluripotent stem cells. Thirdly, the absence of certain nutrients during pregnancy or mutations in one-carbon metabolism can lead to neurodevelopmental disorders in newborns and potentially affecting their growth into adulthood. However, impact on early human development is not well understood. Notably, betaine supplementation is a proven treatment for newborns with some of these conditions. Here, we will utilize human pluripotent stem cells to model how the most common mutations in one-carbon metabolism impact neural differentiation and cellular metabolism. Furthermore, we will study how activation of betaine metabolism can rescue these defects. This research is particularly timely, as it addresses a significant gap in our understanding of the metabolic requirements of pluripotent cells and the molecular mechanisms linking cell metabolism to chromatin modifications in stem cells. This knowledge is essential for comprehending early development and optimizing media formulations for stem cell culture and IVF. One-carbon metabolism is a central biochemical pathway, and maternal vitamin B deficiencies or mutations affecting one-carbon metabolism can lead to metabolic disorders in newborns, associated with neurological, visual, and cardiovascular complications. Thus, this research has potential implications for improving the treatment of disorders associated with faulty metabolism.
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