Sun XiaoYun, Yu WenJun, Li Li, Sun YuHua
The Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
The Innovation of Seed Design, Chinese Academy of Sciences, Wuhan, China.
Front Cell Dev Biol. 2020 Jul 1;8:553. doi: 10.3389/fcell.2020.00553. eCollection 2020.
ADNP (Activity Dependent Neuroprotective Protein) is proposed as a neuroprotective protein whose aberrant expression has been frequently linked to rare neural developmental disorders and cancers, including the recently described neurodevelopmental Helsmoortel-Van der Aa syndrome. Recent studies have suggested that ADNP functions as an important chromatin regulator. However, how ADNP-regulated chromatin mechanisms control gene expression and stem cell fate commitment remains unclear. Here we show that ADNP interacts with two chromatin remodelers, BRG1 and CHD4. ADNP is required for proper establishment of chromatin accessibility, nucleosome configuration, and bivalent histone modifications of developmental genes. Loss of ADNP leads to enhancer over-activation and increased ratio of H3K4me3/H3K27me3 at key primitive endoderm (PrE) gene promoters, resulting in prominent up-regulation of these genes and priming ES cell differentiation toward endodermal cell types. Thus, our work revealed a key role of ADNP in the establishment of local chromatin landscape and structure of developmental genes by association with BRG1 and CHD4. These findings provide further insights into the role of ADNP in the pathology of the Helsmoortel-Van der Aa syndrome.
ADNP（活性依赖神经保护蛋白）被认为是一种神经保护蛋白，其异常表达常与罕见的神经发育障碍和癌症有关，包括最近描述的神经发育障碍Helsmoortel-Van der Aa综合征。最近的研究表明，ADNP作为一种重要的染色质调节因子发挥作用。然而，ADNP调节的染色质机制如何控制基因表达和干细胞命运决定仍不清楚。在这里，我们表明ADNP与两种染色质重塑因子BRG1和CHD4相互作用。ADNP是发育基因染色质可及性、核小体构型和二价组蛋白修饰正常建立所必需的。ADNP的缺失导致增强子过度激活以及关键原始内胚层（PrE）基因启动子处H3K4me3/H3K27me3比值增加，导致这些基因显著上调，并促使胚胎干细胞向内胚层细胞类型分化。因此，我们的工作揭示了ADNP通过与BRG1和CHD4结合在发育基因局部染色质景观和结构建立中的关键作用。这些发现为ADNP在Helsmoortel-Van der Aa综合征病理学中的作用提供了进一步的见解。
