Cell fate determination is a central scientific questions in both cell biology and embryonic development. In recent years, a growing body of research has demonstrated that the differentiation of pluripotent stem cells involves not only systemic remodeling of gene expression programs but also significant transitions in metabolic states. However, how metabolic reprogramming participates in the regulation of cell fate at the molecular level, and how it is coupled with classical signaling pathways and epigenetic mechanisms, remains to be fully elucidated. Particularly in the process of endoderm differentiation, although evidence suggests a metabolic transition from glycolysis to mitochondrial oxidative phosphorylation, the upstream regulatory mechanisms and downstream functional effects of this transition remain unclear.

To address these questions, the research team led by Professor Jiang Wei from our institute recently published a study in  Nature Communications  titled  “TGFβ-activated PDHB promotes mitochondrial pyruvate metabolism and contributes to human endoderm differentiation via ATP-dependent BRG1.”  Using a human pluripotent stem cell (hPSC) differentiation system as a model, the study deciphers the regulatory mechanisms of glucose metabolism reprogramming during endoderm differentiation. It reveals that TGFβ signaling regulates mitochondrial pyruvate metabolism, thereby influencing ATP production and chromatin remodeling, and ultimately drives cell fate transitions at the molecular level.

The study found that glucose metabolism plays a critical role in endoderm differentiation. Increasing glucose concentration significantly promotes the expression of endodermal marker genes, whereas inhibition of glucose metabolism markedly hinders the differentiation process. Further analyses revealed that pyruvate, a crucial intermediate of glucose metabolism, serves as a key driver of differentiation when it enters the mitochondria to participate in the tricarboxylic acid (TCA) cycle. Enhancing pyruvate oxidative metabolism improves differentiation efficiency. Conversely, blocking its transport into the mitochondria causes cells to remain in a glycolytic state characterized by lactate production, which inhibits differentiation. Transcriptomic analyses further showed that genes associated with lactate production are globally downregulated during differentiation, whereas genes involved in the TCA cycle and oxidative phosphorylation are significantly upregulated. These findings confirm a metabolic shift toward mitochondrial oxidative metabolism during this process.

At the mechanistic level, the study further reveals the pivotal role of TGFβ signaling in this metabolic reprogramming process. The results demonstrate that SMAD2/3, the downstream transcription factors of TGFβ, can directly bind to the promoter region of the PDHB gene and promote its expression. As an essential component of the pyruvate dehydrogenase complex, PDHB (Pyruvate Dehydrogenase E1 Subunit Beta) serves as a key node linking glycolysis (lactate production) to the TCA cycle. Functional analyses demonstrate that upregulation of PDHB enhances mitochondrial metabolic activity and promotes endoderm differentiation, whereas Deficiency of PDHB prevents efficient transport of pyruvate into mitochondria, thereby inhibiting the differentiation process. These findings highlight the central role of the TGFβ–PDHB axis in coordinating metabolic regulation and cell differentiation.

Further investigations revealed that the metabolic shift regulate gene expression by influencing chromatin states through ATP levels. Among various metabolic intermediates, only ATP was found to effectively rescue the differentiation defects caused by PDHB deficiency or inhibition of glucose metabolism. Mechanistic analyses demonstrated that ATP functions by modulating ATP-dependent chromatin remodeling complexes. Specifically, BRG1, the core ATPase of the BAF complex, is essential for maintaining an open chromatin state. The study found that inhibiting either BRG1 function or its ATPase activity significantly blocks the differentiation process. Chromatin accessibility analyses further demonstrated that under conditions of reduced ATP levels or PDHB deficiency, the accessibility of regulatory regions of key endodermal genes is significantly decreased, leading to impaired activation of the corresponding gene expression programs.

Furthermore, integrated analysis of single-cell transcriptomic data from early human embryos revealed that during development from the inner cell mass to the epiblast and subsequently to the primitive streak stage, genes associated with glycolysis are progressively downregulated, while genes involved in the TCA cycle and oxidative phosphorylation are continuously upregulated. Meanwhile, the expression of factors related to the BAF complex is concurrently increased. These findings suggest that the metabolic–chromatin regulatory mechanism uncovered in this study is also of significant importance during in vivo embryonic development.

In summary, this study reveals the molecular mechanism by which TGFβ drives the differentiation of human pluripotent stem cells into the endoderm. The process involves the transcriptional activation of PDHB, which promotes the entry of pyruvate into the mitochondria and enhances the TCA cycle and ATP production; this, in turn, regulates chromatin accessibility through the ATP-dependent chromatin remodeling factor BRG1. This work establishes a critical link between metabolic regulation and epigenetic control, providing new insights for understanding the mechanisms of cell fate determination during early human development, as well as offeringvaluable perspectives for stem cell differentiation control and regenerative medicine research.

The research group led by Professor Jiang Wei has long been dedicated to studying the molecular regulatory mechanisms underlying stem cell fate determination and their translational applications. In recent years, the group has made a series of significant advances, including elucidating the roles and mechanisms of epigenetic and RNA regulation in human pluripotency maintenance and germ layer differentiation ( Cell Reports , 2025;  Nature Communications , 2022;  Nucleic Acids Research , 2025/2022;  Genome Biology , 2023;  Nature Chemical Biology , 2025;  Stem Cell Reports , 2025/2020;  Development , 2023;  Cell Regeneration , 2025). The research group has also investigated how intracellular glucose and lipid metabolism, as well as extracellular biomechanical cues, regulate cell differentiation ( Developmental Cell , 2023;  Nature Communications , 2026;  Redox Biology , 2022;  Stem Cell Reports , 2024/2021). Additionally, they have explored the regulatory mechanisms of pancreatic islet differentiation and the role of genetic variation in diabetes susceptibility ( Nature Communications , 2024;  Theranostics , 2022;  Genes & Diseases , 2026). The group has been granted eight national invention patents, and has contributed to writing of three Chinese textbooks/monographs and one English monograph. Students and researchers interested in this field are warmly welcome to join the laboratory.

Original article: https://www.nature.com/articles/s41467-026-69510-0