Autism spectrum disorder (ASD) is a widespread neurodevelopmental disorder with a high degree of genetic heterogeneity, but the etiology remains unknown. In recent years, hundreds of autism-related risk genes have been identified, many of which are directly linked to epigenetic mechanisms. Activity-dependent neuroprotective protein (ADNP) is one of the highest-risk genes for ASD, whose mutations cause ADNP syndrome with an ASD-like phenotype (also known as Helsmoortel-VanDerAa syndrome, HVDAS). In our collection of the largest ADNP mutation cohort in China, we found that a missense mutation close to the zinc finger leads to abnormal ADNP localization and neuronal morphology. In addition, 3D protein structure prediction showed that the structure of the zinc fingers of the mutant was altered. By chromatin immunoprecipitation, we confirmed that the mutant has an altered genome-wide distribution and leads to abnormal GABAergic neuron development by mediating the formation of the H3K27me3/H3K4me3 bivalent domain of NKX2-1, an important regulator of GABAergic neuron development, which may be associated with the development of ASD. Since ADNP is also one of the critical members of the SWI/SNF complex, it may be closely related to chromatin remodeling. We have obtained a full set of epigenetic modifications and Hi-C data from mouse brain, and in the future, we will continue to explore how ADNP regulates the formation of bivalent domains of significant neurodevelopmental genes through the 3D genome and how its abnormalities lead to the development of disease.

ADNP; ASD; Epigenetic; Neuronal development; Bivalent domain