Department of Genetics, Yale Stem Cell Center, Yale Child Study Center, Yale School of Medicine, New Haven, CT, 06520, USA.
Department of Cell Biology, the Second Military Medical University, 200433, Shanghai, China.
Nat Commun. 2018 Jul 3;9(1):2583. doi: 10.1038/s41467-018-04818-0.
Embryonic stem cells (ESCs) maintain pluripotency through unique epigenetic states. When ESCs commit to a specific lineage, epigenetic changes in histones and DNA accompany the transition to specialized cell types. Investigating how epigenetic regulation controls lineage specification is critical in order to generate the required cell types for clinical applications. Uhrf1 is a widely known hemi-methylated DNA-binding protein, playing a role in DNA methylation through the recruitment of Dnmt1 and in heterochromatin formation alongside G9a, Trim28, and HDACs. Although Uhrf1 is not essential in ESC self-renewal, it remains elusive how Uhrf1 regulates cell specification. Here we report that Uhrf1 forms a complex with the active trithorax group, the Setd1a/COMPASS complex, to maintain bivalent histone marks, particularly those associated with neuroectoderm and mesoderm specification. Overall, our data demonstrate that Uhrf1 safeguards proper differentiation via bivalent histone modifications.
胚胎干细胞 (ESCs) 通过独特的表观遗传状态维持多能性。当 ESCs 定向分化为特定谱系时，组蛋白和 DNA 的表观遗传变化伴随着向特化细胞类型的转变。研究表观遗传调控如何控制谱系特化对于产生临床应用所需的细胞类型至关重要。Uhrf1 是一种广泛存在的半甲基化 DNA 结合蛋白，通过募集 Dnmt1 在 DNA 甲基化中发挥作用，并与 G9a、Trim28 和 HDACs 一起形成异染色质。尽管 Uhrf1 在 ESC 自我更新中不是必需的，但 Uhrf1 如何调节细胞特化仍然难以捉摸。在这里，我们报告 Uhrf1 与活性转录激活复合物（trithorax group）、Setd1a/COMPASS 复合物形成复合物，以维持双价组蛋白标记，特别是那些与神经外胚层和中胚层特化相关的标记。总的来说，我们的数据表明 Uhrf1 通过双价组蛋白修饰来确保正确的分化。
