ADNP interacts with a multitude of factors, forming inhibitory complexes that remodel the three-dimensional architecture of chromatin, which in turn influences the regulation of gene expression. The pivotal role played by numerous transposable elements (TEs) in this process remains to be fully elucidated. Our research has revealed that in the brains of ADNP knockout mice during development, there is a substantial increase in the H3K9me3 signals, primarily localized to mouse-specific B2 elements, in conjunction with the previously reported upregulation of CTCF binding signals. Moreover, the global three-dimensional genomic organization within the brains of these knockout mice exhibits significant alterations, which are intimately linked to the epigenetic modifications of H3K9me3. Additionally, at some endogenous retroviruses (ERVs) sites, a decrease in H3K9me3 is observed in parallel with the activation of these ERVs with region-specific manner. We propose that ADNP may modulate the H3K9me3 signals on TEs, either repressing or activating them, which subsequently impacts the expression of development-associated genes and influences the normal developmental trajectory of the mouse brain.

ADNP, H3K9me3, three-dimensional genome, transposable elements