title: DNA N6-methyladenine demethylase ALKBH1 enhances osteogenic differentiation of human MSCs.
abstract: ALKBH1 was recently discovered as a demethylase for DNA N6-methyladenine (N6-mA), a new epigenetic modification, and interacts with the core transcriptional pluripotency network of embryonic stem cells. However, the role of ALKBH1 and DNA N6-mA in regulating osteogenic differentiation is largely unknown. In this study, we demonstrated that the expression of ALKBH1 in human mesenchymal stem cells (MSCs) was upregulated during osteogenic induction. Knockdown of ALKBH1 increased the genomic DNA N6-mA levels and significantly reduced the expression of osteogenic-related genes, alkaline phosphatase activity, and mineralization. ALKBH1-depleted MSCs also exhibited a restricted capacity for bone formationin vivo. By contrast, the ectopic overexpression of ALKBH1 enhanced osteoblastic differentiation. Mechanically, we found that the depletion of ALKBH1 resulted in the accumulation of N6-mA on the promoter region ofATF4, which subsequently silencedATF4transcription. In addition, restoring the expression ofATPby adenovirus-mediated transduction successfully rescued osteogenic differentiation. Taken together, our results demonstrate that ALKBH1 is indispensable for the osteogenic differentiation of MSCs and indicate that DNA N6-mA modifications area new mechanism for the epigenetic regulation of stem cell differentiation.
authors: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, China.
authors: Chenchen
authors: C
authors: Zhou
authors: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, China.
authors: Yuting
authors: 0000-0002-5531-2437
authors: Y
authors: Liu
authors: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, China.
authors: Xiaobing
authors: X
authors: Li
authors: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, China.
authors: Jing
authors: J
authors: Zou
authors: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, China.
authors: Shujuan
authors: S
authors: Zou