Autism risk gene POGZ promotes chromatin accessibility and expression of clustered synaptic genes

• Published in: Cell reports (Cambridge) 2021-12, Vol.37 (10), p.110089-110089, Article 110089
• Main Authors: Markenscoff-Papadimitriou, Eirene, Binyameen, Fadya, Whalen, Sean, Price, James, Lim, Kenneth, Ypsilanti, Athena R., Catta-Preta, Rinaldo, Pai, Emily Ling-Lin, Mu, Xin, Xu, Duan, Pollard, Katherine S., Nord, Alex S., State, Matthew W., Rubenstein, John L.
• Format: Article
• Language: English
• Subjects: Animals; Autistic Disorder - enzymology; Autistic Disorder - genetics; Autistic Disorder - physiopathology; Binding Sites; Brain - enzymology; Brain - growth & development; Cell Cycle Proteins - genetics; Cell Cycle Proteins - physiology; Chromatin Assembly and Disassembly; DNA Transposable Elements; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Enhancer Elements, Genetic; Euchromatin - genetics; Euchromatin - metabolism; Female; Gene Expression Regulation, Developmental; Genetic Predisposition to Disease; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurogenesis; Promoter Regions, Genetic; Synapses - enzymology; Synapses - genetics; Transposases - genetics; Transposases - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.110089

Deleterious genetic variants in POGZ, which encodes the chromatin regulator Pogo Transposable Element with ZNF Domain protein, are strongly associated with autism spectrum disorder (ASD). Although it is a high-confidence ASD risk gene, the neurodevelopmental functions of POGZ remain unclear. Here we reveal the genomic binding of POGZ in the developing forebrain at euchromatic loci and gene regulatory elements (REs). We profile chromatin accessibility and gene expression in Pogz−/− mice and show that POGZ promotes the active chromatin state and transcription of clustered synaptic genes. We further demonstrate that POGZ forms a nuclear complex and co-occupies loci with ADNP, another high-confidence ASD risk gene, and provide evidence that POGZ regulates other neurodevelopmental disorder risk genes as well. Our results reveal a neurodevelopmental function of an ASD risk gene and identify molecular targets that may elucidate its function in ASD. [Display omitted] •POGZ binds enhancers and promoters at euchromatic loci in the developing brain.•POGZ promotes neuronal gene expression and chromatin accessibility.•POGZ forms a nuclear complex with ADNP; Adnp expression is reduced in Pogz+/−.•POGZ bound sites are enriched for other autism risk genes and transposable elements. Markenscoff-Papadimitriou et al. map POGZ occupancy in developing human and mouse brain tissue and find POGZ binds euchromatic loci at promoters and enhancers. Analyses of Pogz−/− mice reveal POGZ specifically promotes the chromatin accessibility and expression of clustered synapse genes, and biochemical analyses show POGZ co-occupies loci with ADNP.