Abstract 2252 ZFP462 safeguards neural lineage specification by targeting G9A/GLP-mediated heterochromatin to silence enhancers

ZNF462 haploinsufficiency is linked to Weiss–Kruszka syndrome, a genetic disorder characterized by neurodevelopmental defects, including autism. However, the molecular functions of ZNF462 are poorly understood. We recently showed that its mouse homolog ZFP462 safeguards neural lineage specification of mouse embryonic stem cells (ESCs) by targeting the H3K9-specific histone methyltransferase complex G9A/GLP to silence meso-endodermal genes. ZFP462 binds to developmental enhancers harboring pluripotency and meso-endoderm transcription factor binding sites. By recruiting G9A/GLP, ZFP462 targets heterochromatin, restricting transcription factor binding. Modeling ZNF462 haploinsufficiency, we generated homozygous and heterozygous Zfp462 deletion mutant ESCs revealing increased DNA accessibility at target sites and ectopic expression of meso-endodermal genes. We conclude that ZFP462 confers lineage and locus specificity to the broadly expressed epigenetic regulator G9A/GLP. Finally, I will present new results showing that ZNF462's role in targeting G9A/GLP-dependent heterochromatin is conserved in human cells. ZNF462 heterozygosity in human ESCs causes loss of heterochromatin and aberrant activation of developmental genes arguing that the defects in neural lineage specification also underlie ZNF462-associated neurodevelopmental pathology. This research was supported by the New Frontiers Group of the Austrian Academy of Sciences (NFG-05) and the National Institute of Mental Health (R01MH122565).