Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
Nat Metab. 2023 Nov;5(11):1911-1930. doi: 10.1038/s42255-023-00916-6. Epub 2023 Nov 16.
Transient reprogramming by the expression of OCT4, SOX2, KLF4 and MYC (OSKM) is a therapeutic strategy for tissue regeneration and rejuvenation, but little is known about its metabolic requirements. Here we show that OSKM reprogramming in mice causes a global depletion of vitamin B and molecular hallmarks of methionine starvation. Supplementation with vitamin B increases the efficiency of reprogramming both in mice and in cultured cells, the latter indicating a cell-intrinsic effect. We show that the epigenetic mark H3K36me3, which prevents illegitimate initiation of transcription outside promoters (cryptic transcription), is sensitive to vitamin B levels, providing evidence for a link between B levels, H3K36 methylation, transcriptional fidelity and efficient reprogramming. Vitamin B supplementation also accelerates tissue repair in a model of ulcerative colitis. We conclude that vitamin B, through its key role in one-carbon metabolism and epigenetic dynamics, improves the efficiency of in vivo reprogramming and tissue repair.
转录因子 OCT4、SOX2、KLF4 和 MYC（OSKM）的瞬时表达是一种组织再生和年轻化的治疗策略，但人们对其代谢需求知之甚少。本文中，我们发现 OSKM 在小鼠体内的重编程会导致维生素 B 的全面耗竭和蛋氨酸饥饿的分子特征。维生素 B 的补充不仅可以提高小鼠体内重编程的效率，也可以提高培养细胞中的重编程效率，这表明存在细胞内在的作用。我们发现，组蛋白 H3K36me3 这种阻止启动子（隐蔽转录）之外转录起始的表观遗传标记对维生素 B 水平敏感，这为 B 水平、H3K36 甲基化、转录保真度和有效的重编程之间的联系提供了证据。维生素 B 的补充还可以加速溃疡性结肠炎模型中的组织修复。我们得出结论，维生素 B 通过其在一碳代谢和表观遗传动态中的关键作用，提高了体内重编程和组织修复的效率。
