Multilayer omics analysis reveals a non-classical retinoic acid signaling axis that regulates hematopoietic stem cell identity.
Multilayer omics analysis reveals a non-classical retinoic acid signaling axis that regulates hematopoietic stem cell identity.
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多层组学分析揭示了调节造血干细胞身份的非经典视黄酸信号轴。
DOI：
10.1016/j.stem.2021.10.002
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发表时间：
2022-01-06
期刊：
影响因子：
23.9
通讯作者：
Cabezas-Wallscheid, Nina
中科院分区：
文献类型：
--
作者：
Schoenberger, Katharina;Obier, Nadine;Romero-Mulero, Mari Carmen;Cauchy, Pierre;Mess, Julian;Pavlovich, Polina, V;Zhang, Yu Wei;Mitterer, Michael;Rettkowski, Jasmin;Lalioti, Maria-Eleni;Jaecklein, Karin;Curtis, Jonathan D.;Feret, Betty;Sommerkamp, Pia;Morganti, Claudia;Ito, Keisuke;Ghyselinck, Norbert B.;Trompouki, Eirini;Buescher, Joerg M.;Pearce, Erika L.;Cabezas-Wallscheid, Nina
造血干细胞（HSC）依赖于复杂的调控网络来保持干细胞。由于HSC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见解。在这项研究中，我们生成了低输入代谢组学、转录组学、染色质可及性和染色质免疫沉淀数据，揭示了富含HSC及其下游多能祖细胞的不同代谢中心。从机制上讲，我们发现了一个非经典的维甲酸（RA）信号轴，调节HSC的功能。我们表明，HSC依赖于Cyp 26 b1，一种通常被认为限制RA在细胞中的作用的酶。与传统观点相反，我们证明Cyp 26 b1对于活性代谢物4-oxo-RA的产生是不可或缺的。此外，RA受体β（Rarb）是4-氧代-RA介导的信号传导的完全传递所需的，以维持干细胞。我们的研究结果强调，一个单一的代谢物控制干细胞的命运，指示表观遗传和转录属性。Schönberger等人生成并整合了纯化造血干细胞（HSC）的低输入多组学数据，以识别与干细胞身份相关的代谢和表观遗传信号中心。从机制上讲，作者发现了一个非经典的类维生素A信号传导轴Cyp 26 b1 -4-oxo-RA-Rarb，对维持HSC特征很重要。
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. Schönberger et al. generate and integrate low-input multi-omics data on purified hematopoietic stem cells (HSCs) to identify metabolic and epigenetic signaling hubs relevant to stem cell identity. Mechanistically, the authors uncover a non-classical retinoid signaling axis, Cyp26b1-4-oxo-RA-Rarb, important for maintenance of HSC features.
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