Centre for Molecular Biology and Neuroscience, Institute of Medical Microbiology, Oslo University Hospital, Rikshospitalet and University of Oslo, Oslo, Norway.
Stem Cells. 2012 Dec;30(12):2672-82. doi: 10.1002/stem.1228.
AlkB homolog 1 (ALKBH1) is one of nine members of the family of mammalian AlkB homologs. Most Alkbh1(-/-) mice die during embryonic development, and survivors are characterized by defects in tissues originating from the ectodermal lineage. In this study, we show that deletion of Alkbh1 prolonged the expression of pluripotency markers in embryonic stem cells and delayed the induction of genes involved in early differentiation. In vitro differentiation to neural progenitor cells (NPCs) displayed an increased rate of apoptosis in the Alkbh1(-/-) NPCs when compared with wild-type cells. Whole-genome expression analysis and chromatin immunoprecipitation revealed that ALKBH1 regulates both directly and indirectly, a subset of genes required for neural development. Furthermore, our in vitro enzyme activity assays demonstrate that ALKBH1 is a histone dioxygenase that acts specifically on histone H2A. Mass spectrometric analysis demonstrated that histone H2A from Alkbh1(-/-) mice are improperly methylated. Our results suggest that ALKBH1 is involved in neural development by modifying the methylation status of histone H2A.
AlkB 同源物 1（ALKBH1）是哺乳动物 AlkB 同源物家族的九个成员之一。大多数 Alkbh1(-/-) 小鼠在胚胎发育过程中死亡，存活下来的小鼠表现出外胚层谱系起源的组织缺陷。在这项研究中，我们表明，Alkbh1 的缺失延长了胚胎干细胞中多能性标记物的表达，并延迟了早期分化相关基因的诱导。与野生型细胞相比，体外分化为神经祖细胞（NPC）时，Alkbh1(-/-) NPC 的细胞凋亡率增加。全基因组表达分析和染色质免疫沉淀显示，ALKBH1 直接和间接调节神经发育所需的一组基因。此外，我们的体外酶活性测定表明，ALKBH1 是一种组蛋白双加氧酶，专门作用于组蛋白 H2A。质谱分析表明，Alkbh1(-/-) 小鼠的组蛋白 H2A 甲基化不当。我们的结果表明，ALKBH1 通过修饰组蛋白 H2A 的甲基化状态参与神经发育。
