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Oligodendroglial hypothesis of autism: the primary role of master regulator gene Baf155 [RNA-Seq]

ABSTRACT: Autism spectrum disorders (ASD) are polyetiological neurodevelopmental disorders associated with both genetic and non-genetic risk factors with complex and heterogeneous clinical manifestations. A single susceptibility gene usually fails in triggering an intricate array of autistic symptoms, suggesting a primary mechanism may be required to integrate multiple susceptibility genes in casing the disease. Recent evidence highlights the role of myeline disruption in pathogenesis of ASD. However, neither the mechanisms of impaired myelination nor its contribution to ASD symptomatology are fully characterized. We demonstrate the loss of Baf155, a newly recognized autistic susceptibility gene that encodes a core member of the chromatin remodeling complex, affects oligodendroglial differentiation and myelination. BAF155 targets multiple synapse-related genes in oligodendrocyte precursor cells (OPCs), these genes being responsible for regulating the synaptic communication between OPCs and neurons. Heterogeneous target genes affected by BAF155 deficiency in OPCs across various brain regions leads to significant impairments in myelination which may contribute to the diverse manifestations observed ASD patients. Taken together, our findings reveal a primary mechanism that orchestrates multiple ASD susceptibility genes in instigating the disease.

ORGANISM(S): Mus musculus Rattus norvegicus

PROVIDER: GSE282099 | GEO | 2025/11/11

REPOSITORIES: GEO

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Project description:Autism spectrum disorder (ASD) is a common, highly heritable neurodevelopmental condition characterized by marked genetic heterogeneity. Thus, a fundamental question is whether autism represents an aetiologically heterogeneous disorder in which the myriad genetic or environmental risk factors perturb common underlying molecular pathways in the brain. Here, we demonstrate consistent differences in transcriptome organization between autistic and normal brain by gene co-expression network analysis. Remarkably, regional patterns of gene expression that typically distinguish frontal and temporal cortex are significantly attenuated in the ASD brain, suggesting abnormalities in cortical patterning. We further identify discrete modules of co-expressed genes associated with autism: a neuronal module enriched for known autism susceptibility genes, including the neuronal specific splicing factor A2BP1 (also known as FOX1), and a module enriched for immune genes and glial markers. Using high-throughput RNA sequencing we demonstrate dysregulated splicing of A2BP1-dependent alternative exons in the ASD brain. Moreover, using a published autism genome-wide association study (GWAS) data set, we show that the neuronal module is enriched for genetically associated variants, providing independent support for the causal involvement of these genes in autism. In contrast, the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic aetiology for this process. Collectively, our results provide strong evidence for convergent molecular abnormalities in ASD, and implicate transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction in this disorder. To identify potential A2BP1-dependent differential splicing events in ASD brain, we performed high-throughput RNA sequencing (RNA-Seq) on three autism samples with significant downregulation of A2BP1 (average fold change by quantitative RT-PCR = 5.9) and three control samples with average A2BP1 levels. The list of potential A2BP1-depending differential splicing events in ASD is given in the Supplementary file linked at the foot of this record.

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Oligodendroglial hypothesis of autism: the primary role of master regulator gene Baf155 [RNA-Seq]

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