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.

提出ADNP（活性依赖性神经保护蛋白）作为一种神经保护蛋白，其异常表达经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性Helsmoortel-Van der Aa综合征。最近的研究表明，ADNP是重要的染色质调节剂。然而，ADNP调节染色质机制如何控制基因表达和干细胞命运承诺仍不清楚。在这里，我们显示ADNP与两个染色质重塑剂BRG1和CHD4相互作用。正确建立染色质可及性，核小体构型和发育基因的二价组蛋白修饰需要ADNP。ADNP的缺失会导致增强子过度激活，并在关键原始内胚层（PrE）基因启动子上增加H3K4me3 / H3K27me3的比例，导致这些基因的显着上调并引发ES细胞向内胚层细胞类型的分化。因此，我们的工作揭示了通过与BRG1和CHD4的结合，ADNP在建立局部染色质景观和发育基因结构中的关键作用。这些发现为ADNP在Helsmoortel-Van der Aa综合征的病理学中的作用提供了进一步的见解。