Summary
Most disease variants lie within noncoding genomic regions, making their functional interpretation challenging. Because chromatin openness strongly influences transcriptional activity, we hypothesized that cell-type-specific open chromatin regions (OCRs) might highlight disease-relevant noncoding sequences. To investigate, we mapped global OCRs in neurons differentiating from hiPSCs, a cellular model for studying neurodevelopmental disorders such as schizophrenia (SZ). We found that the OCRs are highly dynamic and can stratify GWAS-implicated SZ risk variants. Of the more than 3,500 SZ-associated variants analyzed, we prioritized ∼100 putatively functional ones located in neuronal OCRs, including rs1198588, at a leading risk locus flanking MIR137. Excitatory neurons derived from hiPSCs with CRISPR/Cas9-edited rs1198588 or a rare proximally located SZ risk variant showed altered MIR137 expression, dendrite arborization, and synapse maturation. Our study shows that noncoding disease variants in OCRs can affect neurodevelopment, and that analysis of open chromatin regions can help prioritize functionally relevant noncoding variants identified by GWAS.
Nanotechnology-based approaches offer the chemical control required to develop precision tools suitable for applications in neuroscience. We report a novel approach employing hybrid upconversion nanomaterials, combined with the photoresponsive ion channel channelrhodopsin-2 (ChR2), to achieve near infrared light (NIR)-mediated optogenetic control of neuronal activity. Current optogenetic methodologies rely on using visible light (e.g. 470-nm blue light), which tends to exhibit high scattering and low tissue penetration, to activate ChR2. In contrast, our approach enables the use of 980-nm NIR light, which addresses the short-comings of visible light as an excitation source. This was facilitated by embedding upconversion nanomaterials, which can convert NIR light to blue luminescence, into polymeric scaffolds. These hybrid nanomaterial scaffolds allowed for NIR-mediated neuronal stimulation, with comparable efficiency as that of 470-nm blue light. Our platform was optimized for NIR-mediated optogenetic control by balancing multiple physicochemical properties of the nanomaterial (e.g. size, morphology, structure, emission spectra, concentration), thus providing an early demonstration of rationally-designing nanomaterial-based strategies for advanced neural applications.
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