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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE187010 | GEO | 2021/11/05

REPOSITORIES: GEO

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Project description:Purpose: MBD5-Associated Neurodevelopmental Disorder (MAND) is an Autism Spectrum Disorder (ASD) disorder characterized by intellectual disability, motor delay, severe speech impairment and autism-like behavioral problems. The role of MBD5 in neurodevelopmental function remains largely undefined. In this study, we explored the neurodevelopmental phenotype of 2q23.1 deletion syndrome through creating neuronal progenitor stem cells (NPC) derived from 2q23.1 patients and conducting RNA-seq to identify the contributory altered gene and to expand our knowledge about gene network differences and possible interactions between the related disease pathways and ASD. Methods: Primary skin fibroblasts from three MAND patients and four control cases were converted into induced pluripotent stem cell (iPSC) lines by transient transfections of episomal plasmids. Directed differentiation of these iPSC to NPC was accomplished with monolayer culture protocol for two weeks. Results: The RNA-seq analysis identified 498 genome-wide significant (q < 0.05) differentially expressed gene in the patients derived NPC lines as a consequence of reduced MBD5 dosage. 25 ASD associated genes were included in the differentially expressed gene list. On the top of the list, FOXG1 expression is significantly (P < 0.0001) increased in the patient derived NPC samples. The differentially expressed gene list was highly overlapped with the SFARI autism gene set, identifying biological processes that are implicating neurological phenotype and ASD such as central nervous system development, neuron differentiation, and regulation of neurogenesis. The findings of the transcriptome deviation in early neuronal stage of MAND can provide potential connection to the overlapping neurocognitive and neuropsychiatric phenotypes associated with growing risk factors, such as other chromatin modifiers and epigenetic factors that link to ASD. Such in vitro models can nurture hypotheses toward therapeutic interventions.

Project description:Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects more than 1% of children in the USA. ASD risk is thought to arise from both genetic and environmental factors, with the perinatal period as a critical window. Understanding early transcriptional changes in ASD would assist in clarifying disease pathogenesis and identifying biomarkers. However, little is known about umbilical cord blood gene expression profiles in babies later diagnosed with ASD compared to non-typically developing and non-ASD (Non-TD) or typically developing (TD) children. Genome-wide transcript levels were measured by Affymetrix Human Gene 2.0 array in RNA from cord blood samples from both the Markers of Autism Risk in Babies-Learning Early Signs (MARBLES) and the Early Autism Risk Longitudinal Investigation (EARLI) high-risk pregnancy cohorts that enroll younger siblings of a child previously diagnosed with ASD. Younger siblings were diagnosed based on assessments at 36 months, and 59 ASD, 92 Non-TD, and 120 TD subjects were included. Using both differential expression analysis and weighted gene correlation network analysis, gene expression between ASD and TD, and between Non-TD and TD, was compared within each study and via meta-analysis. While cord blood gene expression differences comparing either ASD or Non-TD to TD did not reach genome- wide significance, 172 genes were nominally differentially expressed between ASD and TD cord blood (log2(fold change) > 0.1, p < 0.01). These genes were significantly enriched for functions in xenobiotic metabolism, chromatin regulation, and systemic lupus erythematosus (FDR q < 0.05). In contrast, 66 genes were nominally differentially expressed between Non-TD and TD, including 8 genes that were also differentially expressed in ASD. Gene coexpression modules were significantly correlated with demographic factors and cell type proportions. ASD-associated gene expression differences identified in this study are subtle, as cord blood is not the main affected tissue, it is composed of many cell types, and ASD is a heterogeneous disorder. This is the first study to identify gene expression differences in cord blood specific to ASD through a meta- analysis across two prospective pregnancy cohorts. The enriched gene pathways support involvement of environmental, immune, and epigenetic mechanisms in ASD etiology.

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

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