By: Phillip Wulfridge, John Doherty, Nathaniel Rell, Michelle Lee Lynskey, Kuo-Chen Fang
Author summary The activity-dependent neuroprotective protein (ADNP) plays an important role in brain development and has been widely studied in embryonic stem cells (ESCs). However, studying its function after stem cells differentiate into neural cells has been difficult because ESCs lacking ADNP cannot form neural progenitor cells (NPCs). To overcome this limitation, we developed a model system that allows us to selectively remove ADNP after NPCs have formed. This approach enables us to examine how ADNP functions, where it localizes in the genome, and how it interacts with CTCF, a protein that helps organize the three-dimensional structure of DNA in cells. Using this system, we found that loss of ADNP in NPCs is associated with a genome-wide shift in chromatin organization, leading to changes in local DNA interactions. In NPCs, ADNP is enriched at a new set of genes, where it helps fine-tune the activity of genes that promote neurodifferentiation while repressing genes involved in alternative cell fates. Our findings suggest that ADNP acts through both CTCF-dependent and CTCF-independent mechanisms to regulate chromatin architecture in NPCs and support proper neural development.
