State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
J Biol Chem. 2022 Jan;298(1):101499. doi: 10.1016/j.jbc.2021.101499. Epub 2021 Dec 17.
DNA N6-adenine methylation (6mA), as a novel adenine modification existing in eukaryotes, shows essential functions in embryogenesis and mitochondrial transcriptions. ALKBH1 is a demethylase of 6mA and plays critical roles in osteogenesis, tumorigenesis, and adaptation to stress. However, the integrated biological functions of ALKBH1 still require further exploration. Here, we demonstrate that knockdown of ALKBH1 inhibits adipogenic differentiation in both human mesenchymal stem cells (hMSCs) and 3T3-L1 preadipocytes, while overexpression of ALKBH1 leads to increased adipogenesis. Using a combination of RNA-seq and N6-mA-DNA-IP-seq analyses, we identify hypoxia-inducible factor-1 (HIF-1) signaling as a crucial downstream target of ALKBH1 activity. Depletion of ALKBH1 leads to hypermethylation of both HIF-1α and its downstream target GYS1. Simultaneous overexpression of HIF-1α and GYS1 restores the adipogenic commitment of ALKBH1-deficient cells. Taken together, our data indicate that ALKBH1 is indispensable for adipogenic differentiation, revealing a novel epigenetic mechanism that regulates adipogenesis.
DNA N6-腺嘌呤甲基化（6mA）作为一种存在于真核生物中的新型腺嘌呤修饰，在胚胎发生和线粒体转录中具有重要功能。ALKBH1 是 6mA 的去甲基酶，在成骨、肿瘤发生和应激适应中发挥关键作用。然而，ALKBH1 的综合生物学功能仍需要进一步探索。在这里，我们证明 ALKBH1 的敲低抑制了人间充质干细胞（hMSCs）和 3T3-L1 前脂肪细胞中的脂肪生成分化，而过表达 ALKBH1 则导致脂肪生成增加。通过 RNA-seq 和 N6-mA-DNA-IP-seq 分析的组合，我们确定缺氧诱导因子-1（HIF-1）信号作为 ALKBH1 活性的关键下游靶标。ALKBH1 的耗竭导致 HIF-1α及其下游靶基因 GYS1 的过度甲基化。同时过表达 HIF-1α 和 GYS1 可恢复 ALKBH1 缺陷细胞的脂肪生成能力。总之，我们的数据表明，ALKBH1 对于脂肪生成分化是必不可少的，揭示了一种调节脂肪生成的新的表观遗传机制。
