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Methylation profiling of the chimpanzee CNTNAP2 gene in brain using high-resolution tiling arrays.

ABSTRACT: Accelerated brain development is a unique feature of the human species. Not only the size but also morphology, in particular the connections between frontal cortex and basal ganglia distinguish the human brain from great apes and other primates. Recent findings suggest that structural features which may be important for language acquisition are influenced by FOXP2, key regulator of CNTNAP2. CNTNAP2 is one of the largest genes in the chimpanzee genome, encompassing 2.5 Mb. It encodes a neurexin with essential roles in the vertebrate nervous system. The aim of our study was to compare the methylation patterns of CNTNAP2 in human and chimpanzee brains, assuming that epigenetic regulation is essential for brain development and human language abilities. To this end, we designed a NimbleGen tiling array covering the entire chimpanzee CNTNAP2 gene plus 0.1 Mb up- and downstream flanking sequence with an average resolution of 13 bp. Methylated DNA ImmunoPreciptation (MeDIP) was used to enrich cytosine-methylated DNA fragments for downstream analysis with high-resolution tiling arrays.

ORGANISM(S): Pan troglodytes

PROVIDER: GSE52949 | GEO | 2014/02/20

SECONDARY ACCESSION(S): PRJNA230522

REPOSITORIES: GEO

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Project description:We developed a human cerebral organoid model derived from induced pluripotent stem cells (iPSCs) with targeted genome editing to abolish protein expression of the Contactin Associated Protein-like 2 (CNTNAP2) autism spectrum disorder (ASD) risk gene, mimicking loss-of-function mutations seen in patients. CNTNAP2-/- cerebral organoids displayed accelerated cell cycle, ventricular zone disorganisation and increased cortical folding. Proteomic analysis revealed disruptions in glutamatergic/GABAergic synaptic pathways and neurodevelopment, highlighting increased protein expression of corticogenesis and neurodevelopment-related genes such as Forkhead box protein G1 (FOXG1) and Paired box 6 (PAX6). Transcriptomic analysis revealed differentially expressed genes (DEG) belonging to inhibitory neuron-related gene networks. Interestingly, there was a weak correlation between the transcriptomic and proteomic data, suggesting nuanced translational control mechanisms. Along these lines we find upregulated Protein Kinase B (Akt)/mechanistic target of rapamycin (mTOR) signalling in CNTNAP2-/- organoids. Spatial transcriptomics analysis of CNTNAP2-/- ventricular zones demonstrated pervasive changes in gene expression, particularly in PAX6- cells, implicating upregulation of cell cycle regulation pathways, synaptic and glutamatergic/GABAergic pathways. We noted a significant overlap of all omics datasets with idiopathic ASD (macrocephaly) iPSC-derived telencephalic organoids DEG, where FOXG1 was upregulated, along with aberrant expression of Glutamate decarboxylase 1 (GAD1) and T-Box Brain Transcription Factor 1 (TBR1), suggesting altered GABAergic/glutamatergic neuron development. These findings potentially highlight a shared mechanism in the early cortical development of various forms of ASD, further elucidate the role of CNTNAP2 in ASD pathophysiology and cortical development and pave the way for targeted therapies using cerebral organoids as preclinical models.

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Methylation profiling of the chimpanzee CNTNAP2 gene in brain using high-resolution tiling arrays.

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