Zfp462 Recruits HP1 and Ehmt1/2 to Repress Endodermal Genes in Neuronal Cells

Haploinsufficiency of ZNF462 has recently been shown to cause Weiss-Kruszka Syndrome, a complex neuro-developmental disorder characterized by a spectrum of neurodevelopmental defects including Autism. ZNF462 is a conserved, putative transcription factor that is essential for embryonic development. However, its precise roles in transcriptional regulation and development are not understood. Using a CRISPR genetic screen for regulators of Heterochromatin Protein 1 (HP1)-dependent silencing in mouse embryonic stem cells (mESCs), we discovered that murine homolog Zfp462 is involved in heritable transcriptional silencing through protein interactions with H3K9-specific HMTase G9a/GLP and with Heterochromatin Protein 1 (HP1) isoforms. Zfp462 occupies genomic loci associated with transposable elements (TEs) harboring DNA binding sites for ESC- and endoderm-specific transcription factors (TFs) that are critical for tissue-specific gene expression. Zfp462 deletion in mESCs results in increased chromatin accessibility at target sites and aberrant expression of endodermal genes during neuronal differentiation. We show that Zfp462 controls TE-derived endoderm enhancers by targeting heterochromatin modifiers to restrict TF binding and activation. Together, our data suggest that aberrant activation of endodermal genes interferes with neuronal lineage-specification which may underlie the neurodevelopmental pathology.