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

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. ATAC-seq, and ChIP-seq, and RNA-seq in POGZ knockout and wildtype telencephalic tissues at E13.5. CUT&RUN for POGZ, ADNP, and HP1gamma in E13.5 wildtype mouse telencephalic tissue.POGZ基因编码含锌指（ZNF）结构域的Pogo转座因子类染色质调控蛋白，该基因携带的有害遗传变异与自闭症谱系障碍（ASD）显著相关。尽管POGZ是高置信度的ASD风险基因，但其神经发育功能仍未明确。本研究揭示了POGZ在发育中小鼠前脑的常染色质位点与基因调控元件（REs）上的全基因组结合特征。我们对Pogz基因敲除（Pogz-/-）小鼠的染色质可及性及基因表达谱进行分析，发现POGZ可促进成簇突触相关基因的染色质活化状态与转录过程。本研究进一步证实，POGZ可形成核蛋白复合物，并与另一高置信度ASD风险基因ADNP共同占据基因组位点；同时证明POGZ亦可调控其他神经发育障碍相关风险基因。本研究结果阐明了一款ASD风险基因的神经发育功能，并鉴定出可用于解析其在ASD中作用机制的分子靶点。本研究在小鼠胚胎发育第13.5天（E13.5）的POGZ敲除与野生型端脑组织中开展了转座酶可及性测序（ATAC-seq）、染色质免疫共沉淀测序（ChIP-seq）及RNA测序（RNA-seq）；同时在同期野生型小鼠端脑组织中针对POGZ、ADNP及异染色质蛋白1γ（HP1γ）开展了CUT&RUN实验。