Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; International Max Planck Research School for Molecular and Cellular Biology (IMPRS-MCB), Freiburg, Germany.
Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
Cell Stem Cell. 2022 Jan 6;29(1):131-148.e10. doi: 10.1016/j.stem.2021.10.002. Epub 2021 Oct 26.
Hematopoietic stem cells (HSCs) rely on complex regulatory networks to preserve stemness. Due to the scarcity of HSCs, technical challenges have limited our insights into the interplay between metabolites, transcription, and the epigenome. In this study, we generated low-input metabolomics, transcriptomics, chromatin accessibility, and chromatin immunoprecipitation data, revealing distinct metabolic hubs that are enriched in HSCs and their downstream multipotent progenitors. Mechanistically, we uncover a non-classical retinoic acid (RA) signaling axis that regulates HSC function. We show that HSCs rely on Cyp26b1, an enzyme conventionally considered to limit RA effects in the cell. In contrast to the traditional view, we demonstrate that Cyp26b1 is indispensable for production of the active metabolite 4-oxo-RA. Further, RA receptor beta (Rarb) is required for complete transmission of 4-oxo-RA-mediated signaling to maintain stem cells. Our findings emphasize that a single metabolite controls stem cell fate by instructing epigenetic and transcriptional attributes.
造血干细胞 (HSCs) 依赖于复杂的调控网络来维持其干性。由于 HSCs 的稀缺性，技术挑战限制了我们对代谢物、转录和表观基因组之间相互作用的理解。在这项研究中，我们生成了低投入的代谢组学、转录组学、染色质可及性和染色质免疫沉淀数据，揭示了在 HSCs 及其下游多能祖细胞中富集的独特代谢枢纽。在机制上，我们发现了一个非经典的视黄酸 (RA) 信号轴，它调节 HSC 的功能。我们表明 HSCs 依赖于 Cyp26b1，这是一种通常被认为在细胞中限制 RA 作用的酶。与传统观点相反，我们证明 Cyp26b1 对于产生活性代谢物 4-氧代-RA 是必不可少的。此外，RA 受体β (Rarb) 对于完全传递 4-氧代-RA 介导的信号以维持干细胞是必需的。我们的研究结果强调了单一代谢物通过指导表观遗传和转录特性来控制干细胞命运。
