Orgo-Seq integrates single-cell and bulk transcriptomic data to identify cell type specific-driver genes associated with autism spectrum disorder
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE200851 | GEO | 2022/05/13
REPOSITORIES: GEO
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Project description:Cerebral organoids can be used to gain insights into cell type specific processes perturbed by genetic variants associated with neuropsychiatric disorders. However, robust and scalable phenotyping of organoids remains challenging. Here, we perform RNA sequencing on 71 samples comprising 1,420 cerebral organoids from 25 donors, and describe a framework (Orgo-Seq) to integrate bulk RNA and single-cell RNA sequence data. We apply Orgo-Seq to 16p11.2 deletions and 15q11-13 duplications, two loci associated with autism spectrum disorder, to identify immature neurons and intermediate progenitor cells as critical cell types for 16p11.2 deletions. We further applied Orgo-Seq to identify cell type-specific driver genes. Our work presents a quantitative phenotyping framework to integrate multi-transcriptomic datasets for the identification of cell types and cell type-specific co-expressed driver genes associated with neuropsychiatric disorders.
| S-EPMC9187732 | biostudies-literature
Project description:Autism spectrum disorder (ASD) is a common and etiologically heterogeneous neurodevelopmental disorder. Although many genetic causes have been identified (>200 ASD-risk genes), no single gene mutation accounts for >1% of all ASD cases. A role for epigenetic mechanisms in ASD etiology is supported by the fact that many ASD-risk genes function as epigenetic regulators and evidence that epigenetic dysregulation can interrupt normal brain development. To investigate the epigenome in patients with ASD, genome-wide DNA methylation (DNAm) was assessed using the Illumina Infinium HumanMethylation450K array in blood from individuals with ASD of heterogeneous, undefined etiology (n=52) and individuals with 16p11.2 deletions (16p11.2del, n=9) or pathogenic variants in the chromatin modifier CHD8 (CHD8+/-, n=7), two of the most common genomic variants conferring increased risk for ASD. DNAm patterns did not clearly distinguish heterogeneous ASD cases from controls. However, the homogeneous genetically-defined 16p11.2del and CHD8+/- subgroups each exhibited unique DNAm signatures that distinguished 16p11.2del or CHD8+/- individuals from both heterogeneous ASD and control groups with high sensitivity and specificity. These signatures also classified additional 16p11.2del (n=9) and CHD8 (n=9) variants as pathogenic or benign. Our findings that DNAm alterations in each signature targets unique genes in biological pathways relevant to neural development support their functional relevance. Furthermore, genes identified in our CHD8+/- DNAm signature in blood overlapped differentially expressed genes in CHD8+/- human-induced pluripotent cell-derived neurons and cerebral organoids from independent studies. Our study constitutes a novel approach for ASD molecular classification that elucidates the vital cross-talk between genetics and epigenetics in the etiology of ASD.
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Project description:While the neuronal underpinnings of autism spectrum disorders (ASD) are being unraveled, vascular contributions to ASD remain elusive. Here, we investigated postnatal cerebrovascular development in the 16p11.2df/+ mouse model of 16p11.2 deletion ASD syndrome. We discovered that 16p11.2 hemizygosity leads to male-specific, endothelium-dependent structural and functional neurovascular abnormalities. In 16p11.2df/+ mice, endothelial dysfunction resulted in impaired cerebral angiogenesis at postnatal day (P) 14, and in altered neurovascular coupling and cerebrovascular reactivity at P50. Moreover, we showed defective angiogenesis in primary 16p11.2df/+ mouse brain endothelial cells and in iPSC-derived endothelial cells from human 16p11.2 deletion carriers. Finally, we found that mice with endothelium-specific 16p11.2 deletion (16p11.2DEC) partially recapitulated some behavioral changes seen in 16p11.2 syndrome, specifically hyperactivity and impaired motor learning. By showing that developmental 16p11.2 haploinsufficiency from endothelial cells results in neurovascular and behavioral changes in adults, our results point to a potential role for endothelial impairment in ASD.
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Project description:We recently identified heterozygous deletions of the gene TSHZ3, which encodes a Zn-finger transcription factor, in patients with a syndrome including autistic features and provided evidence in mice for a link between Tshz3 haploinsufficiency, defects in cortical projection neurons (CPNs) and autism spectrum disorder (ASD)-like abnormalities. To get more insight into when and where TSHZ3 is required for the proper development of the brain, we generated and characterized a novel mouse model of conditional Tshz3 deletion in projection neurons from postnatal day 2-3 onward. These mice exhibit altered striatal expression of genes encoding for synaptic components, electrophysiological and synaptic changes in striatal cholinergic interneurons, , as well as ASD-relevant behavioral deficits. These data, by revealing a crucial postnatal role of TSHZ3 in the development and function of the corticostriatal circuitry that might be determinant for ASD pathogenesis, offer a novel ASD model and further open the possibility for an early postnatal therapeutic window for the syndrome linked to TSHZ3 haploinsufficiency.
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Project description:Recurrent Copy Number Variations (CNVs) of human 16p11.2 have been associated with a variety of developmental/neurocognitive syndromes. In particular, deletion of 16p11.2 is found in patients with autism, developmental delay, and obesity. Patients with deletions or duplications have a wide range of clinical features, and siblings carrying the same deletion often have diverse symptoms. To study the consequence of 16p11.2 CNVs in a systematic manner, we used chromosome engineering to generate mice harboring deletion of the chromosomal region corresponding to 16p11.2, as well as mice harboring the reciprocal duplication. These 16p11.2 CNV models have dosage-dependent changes in gene expression, viability, brain architecture, and behavior. For each phenotype, the consequence of the deletion is more severe than that of the duplication. Of particular note is that half of the 16p11.2 deletion mice die postnatally; those that survive to adulthood are healthy and fertile, but have alterations in the hypothalamus and exhibit a ‘behavior trap’ phenotype—a specific behavior characteristic of rodents with lateral hypothalamic and nigrostriatal lesions. Our findings indicate that 16p11.2 CNVs cause both brain and behavioral anomalies, providing new insight into human neurodevelopmental disorders.
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Project description:We recently identified heterozygous deletions of the gene TSHZ3, which encodes a Zn-finger transcription factor, in patients with a syndrome including autistic features and provided evidence in mice for a link between Tshz3 haploinsufficiency, defects in cortical projection neurons (CPNs) and autism spectrum disorder (ASD)-like abnormalities. To get more insight into when and where TSHZ3 is required for the proper development of the brain, we generated and characterized a novel mouse model of conditional Tshz3 deletion in projection neurons from postnatal day 2-3 onward. These mice exhibit altered cortical expression of genes encoding for synaptic components, electrophysiological and synaptic changes in layer 5 CPNs, impaired corticostriatal glutamate transmission and plasticity, as well as strong ASD-relevant behavioral deficits. These data, by revealing a crucial postnatal role of TSHZ3 in the development and function of the corticostriatal circuitry that might be determinant for ASD pathogenesis, offer a novel ASD model and further open the possibility for an early postnatal therapeutic window for the syndrome linked to TSHZ3 haploinsufficiency.
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Project description:Differentiation experiment of mouse embryonic stem cells (ESCs) to neuronal precursor (NPC) and immature dopaminergic neurons (NEU) commited to ventral midbrain lineage. Controls and mutant cell lines harboring heterozygous deletion (del) or duplication-deletion (dupdel) of 7qF3 locus which is synteny conserved with human 16p11.2 locus. Mice harbouring CNVs in this locus display behavioural phenotypes and distinct changes in brain architecture resembling ASD-like traits. Mouse models are described in Guy Horev et al., 2011 (doi: 10.1073/pnas.1114042108). Samples with same numeric identifier were differentiated in parallel.
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Project description:Heterozygous loss-of-function mutations in the synaptic scaffolding gene SHANK2 are strongly associated with autism spectrum disorder (ASD). To investigate their effect on synaptic connectivity, we generated cortical neurons from induced pluripotent stem cells (iPSC) derived from neurotypic and ASD-affected donors. We developed Sparse coculture for Connectivity (SparCon) assays where SHANK2 and control neurons were differentially labeled and sparsely seeded together on a lawn of unlabeled control neurons. We observed striking increases in total synapse number and dendrite complexity. Dendrite length increases were exacerbated by IGF1 or BDNF treatment. Increased excitatory synapse function in haploinsufficient SHANK2 neurons was phenocopied in gene-edited knockout SHANK2 neurons. Gene correction of an ASD SHANK2 mutation rescued excitatory synapse function supporting a role for SHANK2 as a negative regulator of connectivity in developing human neurons. The transcriptome in these isogenic SHANK2 neurons was deeply perturbed in synaptic and plasticity gene sets and ASD gene modules, and activity dependent dendrite extension was defective. Our unexpected findings provide evidence for hyperconnectivity and profoundly altered transcriptome in SHANK2 neurons derived from ASD subjects.
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Project description:Reciprocal deletion and duplication of 16p11.2 is the most common copy number variation (CNV) associated with Autism Spectrum Disorder (ASD) and other developmental disorders, and has significant effect on brain size. We used cortical organoids derived from ASD cases to investigate neurodevelopmental pathways dysregulated by dosage changes of 16p11.2 CNV. We show that organoids recapitulate patients’ macrocephaly and microcephaly phenotypes. Deletions and duplications have “mirror” effects on cell proliferation, maturation and synapse number, consistent with “mirror” effects on brain development in humans. Neuronal migration was decreased in both, deletion and duplication organoids. Transcriptomic and proteomic profiling revealed synaptic defects and neuronal migration as key drivers of 16p11.2 functional effect. We implicate upregulation of small GTPase RhoA involved in regulation of cytoskeletal dynamics, neuron migration and neurite outgrowth as one of the pathways impacted by the 16p11.2 CNV in ASD. Treatment with the RhoA inhibitor Rhosin rescued neuron migration, but not synaptic defects. This study identifies pathways dysregulated by the 16p11.2 CNV during early neocortical development using cortical organoid models. Grant ID: Simons Foundation, #345469 Grant Title: Translational dysregulation of the RhoA pathway in autism Affiliation: University of California San Diego Name: Lilia M. Iakoucheva; Alysson R. Muotri
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