Fig. 3

Overview of ADNP interactions with different chromatin remodelers. (A) General outline of chromatin remodeling, a dynamic process where changes in chromatin architecture can be modified by histone-enzymes such as writers, readers, and erasers. Change in chromatin conformation impacts the transcription machinery, e.g., open chromatin (euchromatin) is associated with gene transcription, while condensed chromatin (heterochromatin) is characterized by repression of transcription. Structural chromatin changes can be inducted by different chromatin remodeling complexes in an ATP-dependent manner, although non-ATP-related alterations have been identified (Box 2). (B) ADNP interacts with the ATP-dependent SWI/SNF (BAF) complex by its C-terminal portion with BRG1, BAF170, and BAF250a, thereby causing aberrant gene expression. (C) ADNP interacts with chromatin remodeler CHD4 by its N-terminus and HP1 by its C-terminus, forming a stable complex called the ChAHP complex, which masks local CTCF-motifs. Locally, the ChAHP complex mediates chromatin condensation at euchromatic regions, repressing stem cell differentiation-related genes. Complete Adnp deficiency results in disruption of the ChAHP complex and exposes the masked CTCF-motifs, normally bound by ChAHP, to introduce novel cohesion-insulated regions, resulting in chromatin recondensation, gene transcription, and spontaneous cell differentiation. (D) ADNP forms a stable triplex with BRG1 and CHD4 (ABC) which strongly binds to inaccessible chromatin. Loss of ADNP increases the ratio H3K4me3/H3K27me3 at key primitive endoderm (PrE) gene promoters, promoting differentiation toward endodermal cells. (E) The ADNP-HP1-POGZ complex is a nuclear repressive complex mediating local chromatin condensation. POGZ had a dual role as activator and repressor of transcription. High levels of POGZ and reduced levels of ADNP cause gene activation, observed as downregulation of proximal genes in Pogz knockout mice, while low POGZ levels and high ADNP levels cause gene repression, shown as upregulation of proximal genes in Pogz knockout mice. (F) In the nucleus, shared promotor region motifs were identified in the ADNP gene with YY1, BRG1 (SMARCA4), and HDAC2, with HDAC2 showing the highest similarity. Recently, WD repeat-containing protein 5 (WDR5) sites were found to be common between ADNP and chromatin modifier SIRT, mediating a nuclear-cytoplasmatic crosstalk and associating with microtubules/Tau