The induction of pluripotent stem cells (iPSCs) by defined factors is poorly understood stepwise. Here, we show that histone H3 lysine 9 (H3K9) methylation is the primary epigenetic determinant for the intermediate pre-iPSC state, and its removal leads to fully reprogrammed iPSCs. We generated a panel of stable pre-iPSCs that exhibit pluripotent properties but do not activate the core pluripotency network, although they remain sensitive to vitamin C for conversion into iPSCs. Bone morphogenetic proteins (BMPs) were subsequently identified in serum as critical signaling molecules in arresting reprogramming at the pre-iPSC state. Mechanistically, we identified H3K9 methyltransferases as downstream targets of BMPs and showed that they function with their corresponding demethylases as the on/off switch for the pre-iPSC fate by regulating H3K9 methylation status at the core pluripotency loci. Our results not only establish pre-iPSCs as an epigenetically stable signpost along the reprogramming road map, but they also provide mechanistic insights into the epigenetic reprogramming of cell fate.

As a metabolic organ, adipose tissue plays an important role in regulating metabolism. In adults, most adipose tissue is white adipose tissue (WAT), and excessive expansion of WAT will lead to obesity. It is worth noting that exercise can reduce the fat mass. There is also a lot of evidence that exercise can promote the browning of WAT, which is beneficial for metabolic homeostasis. Multiple factors, including reactive oxygen species (ROS), metabolites, nervous system, exerkines and lipolysis can facilitate exercise-mediated browning of WAT. In this review, the roles and the underlying mechanisms of exercise-mediated browning of WAT are summarized. The effects of different styles of exercise on the browning of WAT are also discussed, with the aim to propose better exercise strategies to enhance exercise-mediated browning of WAT, so as to promote metabolic health. Finally, the different reactivity of WAT at different anatomical sites to exercise-mediated browning is reviewed, which may provide potential suggestion for people with different fat loss needs.

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