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Placental methylome reveals a 22q13.33 brain regulatory gene locus associated with autism [WGBS]

ABSTRACT: Most autism spectrum disorder (ASD) cases involve complex genetics interacting with perinatal environment, complicating the discovery of common genetic risk. The epigenetic layer of DNA methylation shows dynamic developmental changes and molecular memory of in utero experiences, particularly in placenta, a fetal tissue discarded at birth. However, current array-based methods to identify novel ASD risk genes lack coverage of the most structurally and epigenetically variable regions of the human genome. Here we used whole genome bisulfite sequencing (WGBS) in placenta samples from prospective ASD studies to discover a previously uncharacterized ASD risk gene in a co-methylated block at 22q13.33. Differentially methylated region (DMR) analysis identified 139 DMRs common to ASD in placental samples, including a high-confidence 118 kb hypomethylated block at 22q13.33 that replicated in two additional cohorts and identified the novel transcript NHIP as neuronal hypoxia inducible, placenta associated (gene name approved by HGNC). NHIP characterized by high expression in brain, increased expression following neuronal differentiation or hypoxia in vitro, and minimal expression in ASD placenta. Transient NHIP overexpression in cell lines increased cellular proliferation and altered expression of genes regulating synapses and neurogenesis in response to hypoxia, significantly overlapping with NHIP-associated transcript levels in ASD brain and known ASD risk genes. A common Alu insert near a fetal brain enhancer correlated with NHIP placental and brain expression levels and ASD risk, demonstrating a common genetic influence on DNA methylation levels. Together, these results demonstrate a novel environmentally-responsive ASD risk gene relevant to brain development in a hitherto uncharacterized region of the human genome.

ORGANISM(S): Homo sapiens

PROVIDER: GSE178203 | GEO | 2022/01/16

REPOSITORIES: GEO

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Project description:Prenatal development is a critical period for programming of neurological disease. Preeclampsia, a pregnancy complication involving oxidative stress in the placenta, has been associated with long-term health implications for the child, including an increased risk of developing schizophrenia and autism spectrum disorders in later life. We have shown previously, in a rodent model of placental oxidative stress, that culture medium conditioned by the placenta alters neuronal characteristics when applied to primary cortical cultures in vitro and mimics many of the neurodevelopmental changes observed in the offspring brain. To further investigate if molecules released by the placenta may be important mediators in foetal programming of the brain, we analysed if placental tissue delivered from patients with preeclampsia secreted molecules that could affect cortical cells in culture. Application of culture medium conditioned by preeclamptic placentae to mixed cortical cultures caused changes in neurons and astrocytes that were related to key changes observed in brains of patients with schizophrenia and autism, including effects on dendrite lengths, astrocyte number as well as glutamate and GABA receptors. Treatment of the placental explants with an antioxidant prevented neuronal abnormalities. Furthermore, we identified that bidirectional communication between neurons and astrocytes, potentially via glutamate, is required to produce the effects of preeclamptic placenta medium on cortical cells. Analysis of possible signalling molecules in the placenta conditioned medium showed that the secretion profile of extracellular microRNA, small posttranscriptional regulators, was altered in preeclampsia and partially rescued by antioxidant treatment of the placental explants. Predicted targets of these differentially abundant microRNAs were linked to neurodevelopment and the placenta. The presented study provides further evidence that the diseased placenta may release factors that damage cortical cells in the brain and suggests the possibility of targeted antioxidant treatment of the placenta to prevent neurodevelopmental disorders.

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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Placental methylome reveals a 22q13.33 brain regulatory gene locus associated with autism [WGBS]

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